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| Ref Type | Journal Article | ||||||||||||
| PMID | (32641410) | ||||||||||||
| Authors | Hanrahan AJ, Sylvester BE, Chang MT, Elzein A, Gao J, Han W, Liu Y, Xu D, Gao SP, Gorelick AN, Jones AM, Kiliti AJ, Nissan MH, Nimura CA, Poteshman AN, Yao Z, Gao Y, Hu W, Wise HC, Gavrila EI, Shoushtari AN, Tiwari S, Viale A, Abdel-Wahab O, Merghoub T, Berger MF, Rosen N, Taylor BS, Solit DB | ||||||||||||
| Title | Leveraging Systematic Functional Analysis to Benchmark an In Silico Framework Distinguishes Driver from Passenger MEK Mutants in Cancer. | ||||||||||||
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| Abstract Text | Despite significant advances in cancer precision medicine, a significant hurdle to its broader adoption remains the multitude of variants of unknown significance identified by clinical tumor sequencing and the lack of biologically validated methods to distinguish between functional and benign variants. Here we used functional data on MAP2K1 and MAP2K2 mutations generated in real-time within a co-clinical trial framework to benchmark the predictive value of a three-part in silico methodology. Our computational approach to variant classification incorporated hotspot analysis, three-dimensional molecular dynamics simulation, and sequence paralogy. In silico prediction accurately distinguished functional from benign MAP2K1 and MAP2K2 mutants, yet drug sensitivity varied widely among activating mutant alleles. These results suggest that multifaceted in silico modeling can inform patient accrual to MEK/ERK inhibitor clinical trials, but computational methods need to be paired with laboratory- and clinic-based efforts designed to unravel variabilities in drug response. SIGNIFICANCE: Leveraging prospective functional characterization of MEK1/2 mutants, it was found that hotspot analysis, molecular dynamics simulation, and sequence paralogy are complementary tools that can robustly prioritize variants for biologic, therapeutic, and clinical validation. See related commentary by Whitehead and Sebolt-Leopold, p. 4042 . | ||||||||||||
| Molecular Profile | Treatment Approach |
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| No data available in table | |
| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| No data available in table | |||||
| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| No data available in table | ||||
| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|---|
| MAP2K1 | K35N | missense | no effect - predicted | MAP2K1 K35N does not lie within any known functional domains of the Map2k1 protein (UniProt.org). K35N induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | L42F | missense | gain of function - predicted | MAP2K1 L42F lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). L42F results in autophosphorylation and kinase activity similar to wild-type Map2k1 in in vitro assays (PMID: 29753091), proliferation similar to wild-type in a competition assay, but increased transformation activity (PMID: 36442478) and increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | R49H | missense | no effect - predicted | MAP2K1 R49H lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). R49H results in proliferation similar to wild-type Map2k1 in a competition assay and transformation activity (PMID: 36442478) and Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410) and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | A52V | missense | no effect - predicted | MAP2K1 A52V lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). A52V induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410, PMID: 28115009), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | F53I | missense | gain of function | MAP2K1 F53I lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). F53I results in prolferation in low serum conditions similar to wild-type Map2k1 in a competition assay (PMID: 36442478), but confers a gain of function to Map2k1 as demonstrated by increased Erk phosphorylation in cultured cells (PMID: 32641410), increased proliferation in a competition assay in normal serum conditions, and increased transformation activity in cultured cells (PMID: 36442478). | |
| MAP2K1 | F53V | missense | gain of function | MAP2K1 F53V lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). F53V confers a gain of function to Map2k1 as demonstrated by increased Erk phosphorylation (PMID: 32641410) and transformation activity in cultured cells and increased proliferation in a competition assay (PMID: 36442478). | |
| MAP2K1 | T55P | missense | unknown | MAP2K1 T55P does not lie within any known functional domains of the Map2k1 protein (UniProt.org). T55P results in autophosphorylation levels similar to wild-type Map2k1 in an in vitro assay (PMID: 29753091), but leads to increased Erk phosphorylation in cultured cells in another study (PMID: 32641410), and therefore, its effect on Map2k1 protein function is unknown. | |
| MAP2K1 | K57_G61del | deletion | gain of function - predicted | MAP2K1 K57_G61del results in the deletion of five amino acids of the Map2k1 protein from amino acids 57 to 61 (UniProt.org). K57_G61del results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | K57T | missense | gain of function | MAP2K1 K57T lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). K57T confers a gain of function to Map2k1 as demonstrated by increased Erk1/2 phosphorylation (PMID: 30341394, PMID: 32641410) and transformation activity in cultured cells and increased proliferation in a competition assay (PMID: 36442478), and occurs as a secondary drug resistance mutation in the context of BRAF inhibitors (PMID: 26644315, PMID: 28819429, PMID: 30341394). | Y |
| MAP2K1 | Q58H | missense | no effect - predicted | MAP2K1 Q58H does not lie within any known functional domains of the Map2k1 protein (UniProt.org). Q58H induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | S86A | missense | no effect - predicted | MAP2K1 S86A lies within the protein kinase domain of the Map2k1 protein (UniProt.org). S86A results in Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and transformation activity and proliferation similar to wild-type Map2k1 in cultured cells and a competition assay, respectively (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | A95_R96del | deletion | no effect - predicted | MAP2K1 A95_R96del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 95 to 96 (UniProt.org). A95_R96del induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | R96K | missense | no effect - predicted | MAP2K1 R96K lies within the protein kinase domain of the Map2k1 protein (UniProt.org). R96K results in Erk phosphorylation (PMID: 32641410) and transformation activity similar to wild-type Map2k1 in cultured cells (PMID: 36442478), and proliferation similar to wild-type in a competition assay (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | R96_K97del | deletion | no effect - predicted | MAP2K1 R96_K97del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 96 to 97 (UniProt.org). R96_K97del induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | K97_L98del | deletion | no effect - predicted | MAP2K1 K97_L98del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 97 to 98 (UniProt.org). K97_L98del induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | H100_L101del | deletion | no effect - predicted | MAP2K1 H100_L101del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 100 to 101 (UniProt.org). H100_L101del induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | L101_E102del | deletion | gain of function - predicted | MAP2K1 L101_E102del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 101 to 102 (UniProt.org). L101_E102del results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | I104_P105del | deletion | gain of function - predicted | MAP2K1 I104_P105del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 104 to 105 (UniProt.org). I104_P105del results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | P105_I107delinsL | indel | gain of function - predicted | MAP2K1 P105_I107delinsL results in the deletion of three amino acids in the protein kinase domain of the Map2k1 protein from amino acids 105 to 107, combined with the insertion of a leucine (L) at the same site (UniProt.org). P105_I107delinsL results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | A106_I107del | deletion | gain of function - predicted | MAP2K1 A106_I107del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 106 to 107 (UniProt.org). A106_I107del results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | A106T | missense | no effect - predicted | MAP2K1 A106T lies within the protein kinase domain of the Map2k1 protein (UniProt.org). A106T results in phosphorylation of Erk (PMID: 25164765, PMID: 32641410) and transformation activity similar to wild-type Map2k1 in culture (PMID: 36442478), and proliferation similar to wild-type in a competition assay (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | I107_R108del | deletion | gain of function - predicted | MAP2K1 I107_R108del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 107 to 108 (UniProt.org). I107_R108del results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | R108_N109del | deletion | gain of function - predicted | MAP2K1 R108_N109del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 108 to 109 (UniProt.org). R108_N109del results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | R108Q | missense | no effect - predicted | MAP2K1 R108Q lies within the protein kinase domain of the Map2k1 protein (UniProt.org). R108Q results in Erk phosphorylation (PMID: 32641410) and transformation activity similar to wild-type Map2k1 in culture (PMID: 36442478) and proliferation similar to wild-type in a competition assay (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | N109_Q110del | deletion | gain of function - predicted | MAP2K1 N109_Q110del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 109 to 110 (UniProt.org). N109_Q110del results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | N109_R113del | deletion | gain of function | MAP2K1 N109_R113del results in the deletion of five amino acids in the protein kinase domain of the Map2k1 protein from amino acids 109 to 113 (UniProt.org). N109_R113del confers a gain of function to the Map2k1 protein as indicated by increased Erk phosphorylation (PMID: 32641410, PMID: 30393068), and Mek phosphorylation in cultured cells (PMID: 30393068). | |
| MAP2K1 | Q110_I111del | deletion | gain of function - predicted | MAP2K1 Q110_I111del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 110 to 111 (UniProt.org). Q110_I111del results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | I111_I112del | deletion | gain of function - predicted | MAP2K1 I111_I112del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 111 to 112 (UniProt.org). I111_I112del results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | I112_R113del | deletion | gain of function - predicted | MAP2K1 I112_R113del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 112 to 113 (UniProt.org). I112_R113del results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | R113_E114del | deletion | no effect - predicted | MAP2K1 R113_E114del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 113 to 114 (UniProt.org). R113_E114del induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | E114_L115del | deletion | no effect - predicted | MAP2K1 E114_L115del results in the deletion of two amino acids in the protein kinase domain of the Map2k1 protein from amino acids 114 to 115 (UniProt.org). E114_L115del induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | H119Q | missense | gain of function - predicted | MAP2K1 H119Q lies within the protein kinase domain of the Map2k1 protein (UniProt.org). H119Q results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | H119Y | missense | gain of function - predicted | MAP2K1 H119Y lies within the protein kinase domain of the Map2k1 protein (UniProt.org). H119Y results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | N122D | missense | gain of function - predicted | MAP2K1 N122D lies within the protein kinase domain of the Map2k1 protein (UniProt.org). N122D results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | P124R | missense | gain of function - predicted | MAP2K1 P124R lies within the protein kinase domain of the Map2k1 protein (UniProt.org). P124R results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | Y130H | missense | unknown | MAP2K1 Y130H lies within the protein kinase domain of the Map2k1 protein (UniProt.org). Y130H results in autophosphorylation levels similar to wild-type Map2k1 in an in vitro assay (PMID: 29753091), but leads to increased Erk phosphorylation in cultured cells in another study (PMID: 32641410), and therefore, its effect on Map2k1 protein function is unknown. | |
| MAP2K1 | Y134C | missense | gain of function - predicted | MAP2K1 Y134C lies within the protein kinase domain of the Map2k1 protein (UniProt.org). Y134C results in proliferation similar to wild-type Map2k1 in a competition assay and transformation activity similar to wild-type Map2k1 (PMID: 36442478) but increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | M146I | missense | no effect - predicted | MAP2K1 M146I lies within the protein kinase domain of the Map2k1 protein (UniProt.org). M146I results in Erk phosphorylation (PMID: 32641410), proliferation in a competition assay, and transformation activity similar to wild-type Map2k1 in cultured cells (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | M146T | missense | no effect - predicted | MAP2K1 M146T lies within the protein kinase domain of the Map2k1 protein (UniProt.org). M146T induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | Q164E | missense | no effect - predicted | MAP2K1 Q164E lies within the protein kinase domain of the Map2k1 protein (UniProt.org). Q164E induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | L177M | missense | gain of function | MAP2K1 L177M lies within the protein kinase domain of the Map2k1 protein (UniProt.org). L177M confers a gain of function to the Map2k1 protein as indicated by a moderate increase in basal Erk signaling, sensitivity to Raf pathway activation (PMID: 29483135), and increased Erk phosphorylation in cultured cells (PMID: 32641410). | |
| MAP2K1 | L177V | missense | gain of function - predicted | MAP2K1 L177V lies within the protein kinase domain of the Map2k1 protein (UniProt.org). L177V results in weak phosphorylation of Erk (PMID: 32641410, PMID: 29483135) and phosphorylation of Mek in culture (PMID: 29483135), and therefore, is predicted to lead to a gain of map2k1 protein function. | |
| MAP2K1 | D190Y | missense | no effect - predicted | MAP2K1 D190Y lies within the protein kinase domain of the Map2k1 protein (UniProt.org). D190Y induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | P193S | missense | no effect - predicted | MAP2K1 P193S lies within the protein kinase domain of the Map2k1 protein (UniProt.org). P193S results in Erk phosphorylation (PMID: 32641410), proliferation in a competition assay, and transformation activity similar to wild-type in cultured cells (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | R201C | missense | no effect - predicted | MAP2K1 R201C lies within the protein kinase domain of the Map2k1 protein (UniProt.org). R201C results in Erk phosphorylation (PMID: 32641410), proliferation in a competition assay, and transformation activity similar to wild-type in cultured cells (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | R201H | missense | no effect - predicted | MAP2K1 R201H lies within the protein kinase domain of the Map2k1 protein (UniProt.org). R201H induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | E203D | missense | no effect - predicted | MAP2K1 E203D lies within the protein kinase domain of the Map2k1 protein (UniProt.org). E203D induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | E203V | missense | gain of function - predicted | MAP2K1 E203V lies within the protein kinase domain of the Map2k1 protein (UniProt.org). E203V results in increased Erk phosphorylation in cultured cells (PMID: 32641410), and therefore, is predicted to lead to a gain of Map2k1 protein function. | |
| MAP2K1 | R227K | missense | no effect - predicted | MAP2K1 R227K lies within the protein kinase domain of the Map2k1 protein (UniProt.org). R227K induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | L235H | missense | no effect - predicted | MAP2K1 L235H lies within the protein kinase domain of the Map2k1 protein (UniProt.org). L235H results in Erk phosphorylation (PMID: 32641410) and transformation activity similar to wild-type Map2k1 in culture (PMID: 36442478) and proliferation similar to wild-type in a competition assay (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | V258I | missense | no effect - predicted | MAP2K1 V258I lies within the protein kinase domain of the Map2k1 protein (UniProt.org). V258I induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | P264R | missense | no effect - predicted | MAP2K1 P264R lies within the protein kinase domain of the Map2k1 protein (UniProt.org). P264R induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | P264S | missense | no effect - predicted | MAP2K1 P264S lies within the protein kinase domain of the Map2k1 protein (UniProt.org). P264S results in Erk phosphorylation (PMID: 32641410) and transformation activity similar to wild-type Map2k1 in culture (PMID: 36442478) and proliferation similar to wild-type in a competition assay (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | G294R | missense | no effect - predicted | MAP2K1 G294R lies within the protein kinase domain of the Map2k1 protein (UniProt.org). G294R induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | I310L | missense | no effect - predicted | MAP2K1 I310L lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I310L results in Erk phosphorylation (PMID: 32641410) and transformation activity similar to wild-type Map2k1 in cultured cells, and proliferation similar to wild-type in a competition assay (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | L313F | missense | no effect - predicted | MAP2K1 L313F lies within the protein kinase domain of the Map2k1 protein (UniProt.org). L313F induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | P321H | missense | no effect - predicted | MAP2K1 P321H lies within the protein kinase domain of the Map2k1 protein (UniProt.org). P321H induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | P323A | missense | no effect - predicted | MAP2K1 P323A lies within the protein kinase domain of the Map2k1 protein (UniProt.org). P323A induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | S327T | missense | no effect - predicted | MAP2K1 S327T lies within the protein kinase domain of the Map2k1 protein (UniProt.org). S327T results in Erk phosphorylation (PMID: 32641410) and transformation activity similar to wild-type Map2k1 in cultured cells and proliferation similar to wild-type in a competition assay (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | E333A | missense | no effect - predicted | MAP2K1 E333A lies within the protein kinase domain of the Map2k1 protein (UniProt.org). E333A induces Erk phosphorylation similar to wild-type Map2k1 in cultured cells (PMID: 32641410), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | D336H | missense | no effect - predicted | MAP2K1 D336H lies within the protein kinase domain of the Map2k1 protein (UniProt.org). D336H results in Erk phosphorylation (PMID: 32641410) and transformation activity similar to wild-type Map2k1 in cultured cells, and proliferation similar to wild-type in a competition assay (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. | |
| MAP2K1 | R349K | missense | no effect - predicted | MAP2K1 R349K lies within the protein kinase domain of the Map2k1 protein (UniProt.org). R349K results in Erk phosphorylation (PMID: 32641410) and transformation activity similar to wild-type Map2k1 in cultured cells, and proliferation similar to wild-type in a competition assay (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function. |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| MAP2K1 E102_I103del | Advanced Solid Tumor | predicted - sensitive | SCH772984 | Preclinical - Biochemical | Actionable | In a preclinical study, SCH772984 inhibited downstream signaling in transformed cells expressing MAP2K1 E102_I103del in culture (PMID: 32641410). | 32641410 |
| MAP2K1 E102_I103del | Advanced Solid Tumor | resistant | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, transformed cells expressing MAP2K1 E102_I103del were less sensitive to Mekinist (trametinib) compared to to similar mutations in the negative regulatory domain of the Map2k1 protein in culture (PMID: 32641410). | 32641410 |
| MAP2K1 E203K | Advanced Solid Tumor | predicted - sensitive | SCH772984 | Preclinical - Biochemical | Actionable | In a preclinical study, SCH772984 inhibited downstream signaling in transformed cells expressing MAP2K1 E203K in culture (PMID: 32641410). | 32641410 |
| MAP2K1 F53L | Advanced Solid Tumor | sensitive | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited Erk phosphorylation in transformed cells expressing MAP2K1 F53L in culture (PMID: 32641410). | 32641410 |
| MAP2K1 H119Q | Advanced Solid Tumor | predicted - sensitive | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited Erk phosphorylation in transformed cells expressing MAP2K1 H119Q in culture (PMID: 32641410). | 32641410 |
| MAP2K1 H119Q | Advanced Solid Tumor | predicted - sensitive | SCH772984 | Preclinical - Biochemical | Actionable | In a preclinical study, SCH772984 inhibited downstream signaling in transformed cells expressing MAP2K1 H119Q in culture (PMID: 32641410). | 32641410 |
| MAP2K1 H119Y | Advanced Solid Tumor | predicted - sensitive | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited Erk phosphorylation in transformed cells expressing MAP2K1 H119Y in culture (PMID: 32641410). | 32641410 |
| MAP2K1 I103_K104del | Advanced Solid Tumor | decreased response | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, transformed cells expressing MAP2K1 I103_K104del were less sensitive to Mekinist (trametinib) compared to similar mutations in the negative regulatory domain of the Map2k1 protein in culture (PMID: 32641410). | 32641410 |
| MAP2K1 I103_K104del | Advanced Solid Tumor | predicted - sensitive | SCH772984 | Preclinical - Biochemical | Actionable | In a preclinical study, SCH772984 inhibited downstream signaling in transformed cells expressing MAP2K1 I103_K104del in culture (PMID: 32641410). | 32641410 |
| MAP2K1 I103N | Advanced Solid Tumor | predicted - sensitive | SCH772984 | Preclinical - Biochemical | Actionable | In a preclinical study, SCH772984 inhibited downstream signaling in transformed cells expressing MAP2K1 I103N in culture (PMID: 32641410). | 32641410 |
| MAP2K1 K57N | Advanced Solid Tumor | sensitive | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited Erk phosphorylation in transformed cells expressing MAP2K1 K57N in culture (PMID: 32641410). | 32641410 |
| MAP2K1 K57N | Advanced Solid Tumor | predicted - sensitive | SCH772984 | Preclinical - Biochemical | Actionable | In a preclinical study, SCH772984 inhibited downstream signaling in transformed cells expressing MAP2K1 K57N in culture (PMID: 32641410). | 32641410 |
| MAP2K1 L177M | Advanced Solid Tumor | predicted - sensitive | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited Erk phosphorylation in transformed cells expressing MAP2K1 L177M in culture (PMID: 32641410). | 32641410 |
| MAP2K1 L177M | Advanced Solid Tumor | predicted - sensitive | SCH772984 | Preclinical - Biochemical | Actionable | In a preclinical study, SCH772984 inhibited downstream signaling in transformed cells expressing MAP2K1 L177M in culture (PMID: 32641410). | 32641410 |
| MAP2K1 L42F | Advanced Solid Tumor | predicted - sensitive | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited Erk phosphorylation in transformed cells expressing MAP2K1 L42F in culture (PMID: 32641410). | 32641410 |
| MAP2K1 N109_R113del | Advanced Solid Tumor | predicted - sensitive | SCH772984 | Preclinical - Biochemical | Actionable | In a preclinical study, SCH772984 inhibited downstream signaling in transformed cells expressing MAP2K1 N109_R113del in culture (PMID: 32641410). | 32641410 |
| MAP2K1 N109_R113del | Advanced Solid Tumor | predicted - sensitive | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited Erk phosphorylation in transformed cells expressing MAP2K1 N109_R113del in culture (PMID: 32641410). | 32641410 |
| MAP2K1 N122D | Advanced Solid Tumor | predicted - sensitive | SCH772984 | Preclinical - Biochemical | Actionable | In a preclinical study, SCH772984 inhibited downstream signaling in transformed cells expressing MAP2K1 N122D in culture (PMID: 32641410). | 32641410 |
| MAP2K1 P105_A106del | Advanced Solid Tumor | predicted - sensitive | SCH772984 | Preclinical - Biochemical | Actionable | In a preclinical study, SCH772984 inhibited downstream signaling in transformed cells expressing MAP2K1 P105_A106del in culture (PMID: 32641410). | 32641410 |
| MAP2K1 P105_A106del | Advanced Solid Tumor | resistant | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, transformed cells expressing MAP2K1 P105_A106del were less sensitive to Mekinist (trametinib) compared to similar mutations in the negative regulatory domain of the Map2k1 protein in culture (PMID: 32641410). | 32641410 |
| MAP2K1 P105_I107delinsL | Advanced Solid Tumor | predicted - sensitive | SCH772984 | Preclinical - Biochemical | Actionable | In a preclinical study, SCH772984 inhibited downstream signaling in transformed cells expressing MAP2K1 P105_I107delinsL in culture (PMID: 32641410). | 32641410 |
| MAP2K1 P105_I107delinsL | Advanced Solid Tumor | decreased response | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, transformed cells expressing MAP2K1 P105_I107delinsL were less sensitive to Mekinist (trametinib) compared to similar mutations in the negative regulatory domain of the Map2k1 protein in culture (PMID: 32641410). | 32641410 |
| MAP2K1 Q56P | Advanced Solid Tumor | sensitive | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited Erk phosphorylation in transformed cells expressing MAP2K1 Q56P in culture (PMID: 32641410). | 32641410 |
| MAP2K1 T55P | Advanced Solid Tumor | predicted - sensitive | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited Erk phosphorylation in transformed cells expressing MAP2K1 T55P in culture (PMID: 32641410). | 32641410 |
| MAP2K1 V60E | Advanced Solid Tumor | sensitive | Trametinib | Preclinical - Biochemical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited Erk phosphorylation in transformed cells expressing MAP2K1 V60E in culture (PMID: 32641410). | 32641410 |
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