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Journal Article

PMID

(22389471)

Authors

Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, Smitheman KN, Dickerson SH, Laquerre SG, Liu L, Gilmer TM

Title

Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	11	4	2012 Apr	909-20	Mol Cancer Ther

URL

Abstract Text

Recent results from clinical trials with the BRAF inhibitors GSK2118436 (dabrafenib) and PLX4032 (vemurafenib) have shown encouraging response rates; however, the duration of response has been limited. To identify determinants of acquired resistance to GSK2118436 and strategies to overcome the resistance, we isolated GSK2118436 drug-resistant clones from the A375 BRAF(V600E) and the YUSIT1 BRAF(V600K) melanoma cell lines. These clones also showed reduced sensitivity to the allosteric mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor GSK1120212 (trametinib). Genetic characterization of these clones identified an in-frame deletion in MEK1 (MEK1(K59del)) or NRAS mutation (NRAS(Q61K) and/or NRAS(A146T)) with and without MEK1(P387S) in the BRAF(V600E) background and NRAS(Q61K) in the BRAF(V600K) background. Stable knockdown of NRAS with short hairpin RNA partially restored GSK2118436 sensitivity in mutant NRAS clones, whereas expression of NRAS(Q61K) or NRAS(A146T) in the A375 parental cells decreased sensitivity to GSK2118436. Similarly, expression of MEK1(K59del), but not MEK1(P387S), decreased sensitivity of A375 cells to GSK2118436. The combination of GSK2118436 and GSK1120212 effectively inhibited cell growth, decreased ERK phosphorylation, decreased cyclin D1 protein, and increased p27(kip1) protein in the resistant clones. Moreover, the combination of GSK2118436 or GSK1120212 with the phosphoinositide 3-kinase/mTOR inhibitor GSK2126458 enhanced cell growth inhibition and decreased S6 ribosomal protein phosphorylation in these clones. Our results show that NRAS and/or MEK mutations contribute to BRAF inhibitor resistance in vitro, and the combination of GSK2118436 and GSK1120212 overcomes this resistance. In addition, these resistant clones respond to the combination of GSK2126458 with GSK2118436 or GSK1120212. Clinical trials are ongoing or planned to test these combinations.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
MAP2K1	K59del	deletion	unknown	MAP2K1 K59del results in the deletion of an amino acid in the protein kinase domain of the Map2k1 protein at amino acid 59 (UniProt.org). K59del results in increased Mek and Erk phosphorylation in culture (PMID: 22389471), but demonstrates autophosphorylation levels similar to wild-type Map2k1 in another study (PMID: 29753091), and therefore, its effect on Map2k1 protein function is unknown.
NRAS	A146T	missense	gain of function	NRAS A146T does not lie within any known functional domains of the Nras protein (UniProt.org). A146T results in increased Nras activity likely due to increased GDP/GTP exchange rate, activation of downstream signaling, and is identified as a secondary mutation conferring resistance to Braf and Mek inhibitors in culture (PMID: 22389471, PMID: 3043178).	Y
MAP2K1	P387S	missense	gain of function	MAP2K1 P387S does not lie within any known functional domains of the Map2k1 protein (UniProt.org). P387S confers a gain of function to the Map2k1 protein as demonstrated by constitutive phosphorylation of Mek and Erk (PMID: 22389471).

Showing 1 to 3 of 3 entries

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Showing 1 to 48 of 48 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600K NRAS Q61K	melanoma	predicted - sensitive	GSK2126458	Preclinical - Cell culture	Actionable	In a preclinical study, Omipalisib (GSK2126458) inhibited the growth of melanoma cell lines harboring BRAF V600K with NRAS Q61K in culture (PMID: 22389471).	22389471
BRAF V600E	melanoma	sensitive	Dabrafenib + GSK2126458	Preclinical	Actionable	In a preclinical study, Tafinlar (dabrafenib) in combination with Omipalisib (GSK2126458) resulted in improved growth inhibition of human melanoma cell lines harboring BRAF V600E in culture (PMID: 22389471).	22389471
BRAF V600E	melanoma	sensitive	Dabrafenib + Trametinib	Preclinical	Actionable	In a preclinical study, Tafinlar (dabrafenib) in combination with Mekinist (trametinib) inhibited growth of melanoma cells harboring BRAF V600E in culture (PMID: 22389471).	22389471
BRAF V600E	melanoma	sensitive	GSK2126458 + Trametinib	Preclinical	Actionable	In a preclinical study, Mekinist (trametinib) in combination with Omipalisib (GSK2126458) inhibited growth of melanoma cell lines harboring BRAF V600E in culture (PMID: 22389471).	22389471
BRAF V600E	melanoma	sensitive	GSK2126458	Preclinical	Actionable	In a preclinical study, Omipalisib (GSK2126458) inhibited the growth of melanoma cell lines harboring BRAF V600E in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 K59del	melanoma	resistant	Trametinib	Preclinical	Actionable	In a preclinical study, human melanoma cell lines harboring BRAF V600E and MAP2K1 K59del were resistant to growth inhibition by Mekinist (trametinib) in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 K59del	melanoma	sensitive	Dabrafenib + Trametinib	Preclinical	Actionable	In a preclinical study, Talfinlar (dabrafenib) in combination with Mekinist (trametinib) resulted in improved growth inhibition of human melanoma cell lines harboring BRAF V600E harboring MAP2K1 K59del in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 K59del	melanoma	decreased response	GSK2126458	Preclinical	Actionable	In a preclinical study, human melanoma cell lines harboring BRAF V600E and MAP2K1 K59del had reduced sensitivity to Omipalisib (GSK2126458) in comparison to parental cell lines harboring BRAF V600E in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 K59del	melanoma	resistant	Vemurafenib	Preclinical	Actionable	In a preclinical study, human melanoma cell lines harboring BRAF V600E and MAP2K1 K59del were resistant to Zelboraf (vemurafenib) growth inhibition in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 K59del	melanoma	sensitive	Dabrafenib + GSK2126458	Preclinical	Actionable	In a preclinical study, Tafinlar (dabrafenib) in combination with Omipalisib (GSK2126458) resulted in improved growth inhibition of human melanoma cell lines harboring BRAF V600E and MAP2K1 K59del in culture, compared to either agent alone (PMID: 22389471).	22389471
BRAF V600E MAP2K1 K59del	melanoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, human melanoma cell lines harboring BRAF V600E and MAP2K1 K59del were resistant to Tafinlar (dabrafenib) mediated growth inhibition in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 K59del	melanoma	sensitive	GSK2126458 + Trametinib	Preclinical	Actionable	In a preclinical study, Mekinist (trametinib) in combination with Omipalisib (GSK2126458) resulted in improved growth inhibition of human melanoma cell lines harboring BRAF V600E and MAP2K1 K59del in culture, compared to either agent alone (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS A146T	melanoma	no benefit	Dabrafenib + GSK2126458	Preclinical	Actionable	In a preclinical study, Talfinlar (dabrafenib) in combination with Omipalisib (GSK2126458) did not improve the response to human melanoma cell lines harboring BRAF V600E, NRAS A146T and MAP2K1 P387S in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS A146T	melanoma	decreased response	GSK2126458	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E, NRAS A146T and MAP2K1 P387S had reduced sensitivity to Omipalisib (GSK2126458) in comparison to parental cell lines harboring BRAF V600E in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS A146T	melanoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, human melanoma cell lines harboring BRAF V600E, NRAS A146T and MAP2K1 P387S were resistant to Tafinlar (dabrafenib) mediated growth inhibition in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS A146T	melanoma	resistant	Vemurafenib	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E, NRAS A146T and MAP2K1 P387S were resistant to Zelboraf (vemurafenib) growth inhibition in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS A146T	melanoma	decreased response	Trametinib	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E, NRAS A146T and MAP2K1 P387S were >20-fold less sensitive to growth inhibition by Mekinist (trametinib) than parental cell lines harboring BRAF V600E and also had reduced sensitivity in comparison to cell lines harboring BRAF V600E and NRAS A146T in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS A146T	melanoma	sensitive	GSK2126458 + Trametinib	Preclinical	Actionable	In a preclinical study, Mekinist (trametinib) in combination with Omipalisib (GSK2126458) resulted in improved growth inhibition in melanoma cell lines harboring BRAF V600E, NRAS A146T and MAP2K1 P387S in culture, compared to either agent alone (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS Q61K	melanoma	decreased response	GSK2126458	Preclinical	Actionable	In a preclinical study, human melanoma cell lines harboring BRAF V600E, NRAS Q61K and MAP2K1 P387S had reduced sensitivity to Omipalisib (GSK2126458) in comparison to parental cell lines harboring BRAF V600E in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS Q61K	melanoma	sensitive	GSK2126458 + Trametinib	Preclinical	Actionable	In a preclinical study, Mekinist (trametinib) in combination with Omipalisib (GSK2126458) resulted in improved growth inhibition of human melanoma cell lines harboring BRAF V600E, NRAS Q61K, and MAP2K1 P387S in culture, compared to either agent alone (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS Q61K	melanoma	conflicting	Dabrafenib + GSK2126458	Preclinical	Actionable	In a preclinical study, the response of human melanoma cell lines harboring BRAF V600E, NRAS Q61K, and MAP2K1 P387S to Tafinlar (dabrafenib) in combination with Omipalisib (GSK2126458) was conflicting as one cell line with this mutation profile responded to the combination and another cell line with the mutation profile did not (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS Q61K	melanoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, human melanoma cell lines harboring BRAF V600E, NRAS Q61K and MAP2K1 P387S were resistant to Tafinlar (dabrafenib) mediated growth inhibition in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS Q61K	melanoma	decreased response	Trametinib	Preclinical	Actionable	In a preclinical study, human melanoma cell lines harboring BRAF V600E, NRAS Q61K and MAP2K1 P387S were >20-fold less sensitive to growth inhibition by Mekinist (trametinib) than parental cell lines harboring BRAF V600E in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS Q61K	melanoma	resistant	Vemurafenib	Preclinical	Actionable	In a preclinical study, human melanoma cell lines harboring BRAF V600E, NRAS Q61K and MAP2K1 P387S were resistant to growth inhibition by Zelboraf (vemurafenib) in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS Q61K NRAS A146T	melanoma	resistant	Trametinib	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E, NRAS Q61K, NRAS A146T and MAP2K1 P387S were resistant to growth inhibition by Mekinist (trametinib) in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS Q61K NRAS A146T	melanoma	decreased response	GSK2126458	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E, NRAS Q61K, NRAS A146T and MAP2K1 P387S had reduced sensitivity to Omipalisib (GSK2126458) in comparison to parental cell lines harboring BRAF V600E in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS Q61K NRAS A146T	melanoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E, NRAS Q61K, NRAS A146T and MAP2K1 P387S were resistant Tafinlar (dabrafenib) mediated growth inhibition in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS Q61K NRAS A146T	melanoma	sensitive	GSK2126458 + Trametinib	Preclinical	Actionable	In a preclinical study, Mekinist (trametinib) in combination with Omipalisib (GSK2126458) resulted in improved growth inhibition in melanoma cell lines harboring BRAF V600E, NRAS Q61K, NRAS A146T and MAP2K1 P387S in culture, compared to either agent alone (PMID: 22389471).	22389471
BRAF V600E MAP2K1 P387S NRAS Q61K NRAS A146T	melanoma	resistant	Vemurafenib	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E, NRAS Q61K, A146T and MAP2K1 P387S were resistant to Zelboraf (vemurafenib) growth inhibition in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 Q56P	melanoma	conflicting	Trametinib	Preclinical	Actionable	In a preclinical study, human melanoma cell lines harboring BRAF V600E expressing MAP2K1 Q56P displayed reduced sensitivity to Mekinist (trametinib) mediated growth inhibition and retained MEK and ERK signaling (PMID: 22389471).	22389471
BRAF V600E MAP2K1 Q56P	melanoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E expressing MAP2K1 Q56P were resistant to Tafinlar (dabrafenib) mediated growth inhibition and retained MEK and ERK signaling in culture (PMID: 22389471).	22389471
BRAF V600E MAP2K1 Q56P	melanoma	sensitive	Dabrafenib + Trametinib	Preclinical	Actionable	In a preclinical study, the combination of Talfinlar (dabrafenib) and Mekinist (trametinib) resulted in improved growth inhibition in melanoma cells harboring BRAF V600E and expressing MAP2K1 Q56P in culture (PMID: 22389471).	22389471
BRAF V600E NRAS A146T	melanoma	sensitive	Dabrafenib + GSK2126458	Preclinical	Actionable	In a preclinical study, Talfinlar (dabrafenib) in combination with Omipalisib (GSK2126458) resulted in improved growth inhibition of human melanoma cell lines harboring BRAF V600E and NRAS A146T in culture, compared to either agent alone (PMID: 22389471).	22389471
BRAF V600E NRAS A146T	melanoma	sensitive	GSK2126458 + Trametinib	Preclinical	Actionable	In a preclinical study, Mekinist (trametinib) in combination with Omipalisib (GSK2126458) resulted in improved growth inhibition in melanoma cell lines harboring BRAF V600E and NRAS A146T in culture, compared to either agent alone (PMID: 22389471).	22389471
BRAF V600E NRAS A146T	melanoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, human melanoma cell lines harboring BRAF V600E and NRAS A146T were resistant to Tafinlar (dabrafenib) growth inhibition in culture (PMID: 22389471).	22389471
BRAF V600E NRAS A146T	melanoma	sensitive	Dabrafenib + Trametinib	Preclinical	Actionable	In a preclinical study, Tafinlar (dabrafenib) in combination with Mekinist (trametinib) resulted in improved growth inhibition of melanoma cell lines harboring BRAF V600E and NRAS A146T in culture, compared to either agent alone (PMID: 22389471).	22389471
BRAF V600E NRAS A146T	melanoma	decreased response	GSK2126458	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E and NRAS A146T had reduced sensitivity to Omipalisib (GSK2126458) in comparison to parental cell lines harboring BRAF V600E in culture (PMID: 22389471).	22389471
BRAF V600E NRAS A146T	melanoma	resistant	Vemurafenib	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E and NRAS A146T were resistant to Zelboraf (vemurafenib) growth inhibition in culture (PMID: 22389471).	22389471
BRAF V600E NRAS A146T	melanoma	decreased response	Trametinib	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E and NRAS A146T were >10-fold less sensitive to growth inhibition by Mekinist (trametinib) than parental cell lines harboring BRAF V600E in culture (PMID: 22389471).	22389471
BRAF V600E NRAS Q61K	melanoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, human melanoma cell lines harboring BRAF V600E expressing NRAS Q61K were resistant to Tafinlar (dabrafenib) mediated growth inhibition and retained MEK and ERK signaling (PMID: 22389471).	22389471
BRAF V600E NRAS Q61K	melanoma	sensitive	Dabrafenib + Trametinib	Preclinical	Actionable	In a preclinical study, Talfinlar (dabrafenib) in combination with Mekinist (trametinib) resulted in improved growth inhibition of melanoma cell lines harboring BRAF V600E and NRAS Q61K in culture, compared to either agent alone (PMID: 22389471).	22389471
BRAF V600E NRAS Q61K NRAS A146T	melanoma	sensitive	Dabrafenib + Trametinib	Preclinical	Actionable	In a preclinical study, Talfinlar (dabrafenib) in combination with Mekinist (trametinib) resulted in improved growth inhibition of human melanoma cells harboring BRAF V600E and NRAS A146T and NRAS Q61K in culture (PMID: 22389471).	22389471
BRAF V600K	melanoma	sensitive	GSK2126458	Preclinical	Actionable	In a preclinical study, Omipalisib (GSK2126458) inhibited the growth of melanoma cell lines harboring BRAF V600K in culture (PMID: 22389471).	22389471
BRAF V600K NRAS Q61K	melanoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600K and NRAS Q61K were resistant to Tafinlar (dabrafenib) growth inhibition in culture (PMID: 22389471).	22389471
BRAF V600K NRAS Q61K	melanoma	sensitive	GSK2126458 + Trametinib	Preclinical	Actionable	In a preclinical study, Mekinist (trametinib) in combination with Omipalisib (GSK2126458) resulted in improved growth inhibition in melanoma cell lines harboring BRAF V600K and NRAS Q61K in culture, compared to either agent alone (PMID: 22389471).	22389471
BRAF V600K NRAS Q61K	melanoma	decreased response	Trametinib	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600K and NRAS Q61K were 3-7 fold less sensitive to growth inhibition by Mekinist (trametinib) than parental cell lines harboring BRAF V600K in culture (PMID: 22389471).	22389471
BRAF V600K NRAS Q61K	melanoma	sensitive	Dabrafenib + GSK2126458	Preclinical	Actionable	In a preclinical study, Tafinlar (dabrafenib) in combination with Omipalisib (GSK2126458) resulted in improved growth inhibition of human melanoma cell lines harboring BRAF V600K and NRAS Q61K in culture (PMID: 22389471).	22389471
BRAF V600K NRAS Q61K	melanoma	sensitive	Dabrafenib + Trametinib	Preclinical	Actionable	In a preclinical study, Tafinlar (dabrafenib) in combination with Mekinist (trametinib) inhibited growth of melanoma cell lines harboring BRAF V600K and NRAS Q61K in culture (PMID: 22389471).	22389471

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