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Ref Type | Journal Article | ||||||||||||
PMID | (26343583) | ||||||||||||
Authors | Peng SB, Henry JR, Kaufman MD, Lu WP, Smith BD, Vogeti S, Rutkoski TJ, Wise S, Chun L, Zhang Y, Van Horn RD, Yin T, Zhang X, Yadav V, Chen SH, Gong X, Ma X, Webster Y, Buchanan S, Mochalkin I, Huber L, Kays L, Donoho GP, Walgren J, McCann D, Patel P, Conti I, Plowman GD, Starling JJ, Flynn DL | ||||||||||||
Title | Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers. | ||||||||||||
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Abstract Text | LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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No data available in table |
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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LY3009120 | DP-4978 | RAF Inhibitor (Pan) 29 | LY3009120 is a Pan-RAF inhibitor that inhibits signaling of all RAF isoforms and RAF dimers, which leads to inhibition of tumor cell growth (PMID: 26343583, PMID: 28576749). |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
---|---|---|---|---|---|
NRAS | R167L | missense | unknown | NRAS R167L lies within the hypervariable region of the Nras protein (UniProt.org). R167L has been identified in the scientific literature (PMID: 26343583), but has not been biochemically characterized and therefore, its effect on Nras protein function is unknown (PubMed, Dec 2024). |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
BRAF G469R NRAS Q61K | melanoma | resistant | Vemurafenib | Preclinical - Cell culture | Actionable | In a preclinical study, human melanoma cells harboring BRAF G469R and NRAS Q61K were insensitive to Zelboraf (vemurafenib) in culture (PMID: 26343583). | 26343583 |
BRAF G469R NRAS Q61K | melanoma | decreased response | Selumetinib | Preclinical | Actionable | In a preclinical study, Selumetinib (AZD6244) modestly inhibited proliferation of human melanoma cells harboring BRAF G469R and NRAS Q61K in culture (PMID: 26343583). | 26343583 |
BRAF G469R NRAS Q61K | melanoma | sensitive | LY3009120 | Preclinical | Actionable | In a preclinical study, LY3009120 inhibited soft agar growth of human melanoma cancer cells harboring BRAF G469R and NRAS Q61K in culture (PMID: 26343583). | 26343583 |
BRAF mutant | colorectal cancer | resistant | Trametinib | Preclinical | Actionable | In a preclinical study, a majority of human colorectal cancer cell lines (4/7) harboring mutant BRAF were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). | 26343583 |
BRAF mutant | lung adenocarcinoma | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of lung adenocarcinoma cells harboring mutant BRAF in culture (PMID: 26343583). | 26343583 |
BRAF mutant | multiple myeloma | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human multiple myeloma cells harboring mutant BRAF in culture (PMID: 26343583). | 26343583 |
BRAF mutant | pancreatic adenocarcinoma | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human pancreatic adenocarcinoma cells harboring mutant BRAF in culture (PMID: 26343583). | 26343583 |
BRAF V600E | melanoma | sensitive | LY3009120 | Preclinical | Actionable | In a preclinical study, LY3009120 inhibited growth, downstream MAPK signaling and soft agar growth in human melanoma cell lines harboring BRAF V600E in culture (PMID: 26343583). | 26343583 |
CDKN2A mut NRAS act mut | acute lymphoblastic leukemia | resistant | Trametinib | Preclinical | Actionable | In a preclinical study, human acute lymphoblastic leukemia cells harboring NRAS and CDKN2A mutations were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). | 26343583 |
CTNNB1 mut NRAS mut | liver cancer | resistant | Trametinib | Preclinical | Actionable | In a preclinical study, human liver cancer cells harboring mutant NRAS and mutant CTNNB1 were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). | 26343583 |
HRAS mutant | endometrial cancer | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human endometrial cancer cells harboring mutant HRAS in culture (PMID: 26343583). | 26343583 |
HRAS mutant | transitional cell carcinoma | resistant | Trametinib | Preclinical | Actionable | In a preclinical study, human urinary transitional cell carcinoma cells harboring mutant HRAS were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). | 26343583 |
NRAS G13D | melanoma | sensitive | Selumetinib | Preclinical | Actionable | In a preclinical study, Selumetinib (AZD6244) inhibited proliferation of human melanoma cells harboring NRAS G13D in culture (PMID: 26343583). | 26343583 |
NRAS G13D | melanoma | resistant | Vemurafenib | Preclinical | Actionable | In a preclinical study, human melanoma cells harboring NRAS G13D were insensitive to Zelboraf (vemurafenib) in culture (PMID: 26343583). | 26343583 |
NRAS G13D | melanoma | sensitive | LY3009120 | Preclinical | Actionable | In a preclinical study, LY3009120 inhibited soft agar growth of human melanoma cancer cells harboring NRAS G13D in culture (PMID: 26343583). | 26343583 |
NRAS mutant | ovarian cancer | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of ovarian cancer cells harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
NRAS mutant | autonomic nervous system neoplasm | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human autonomic ganglia cancer cells harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
NRAS mutant | central nervous system cancer | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human central nervous system cancer cells harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
NRAS mutant | melanoma | sensitive | LY3009120 | Preclinical | Actionable | In a preclinical study, LY3009120 inhibited growth of NRAS mutant human melanoma cell lines in culture (PMID: 26343583). | 26343583 |
NRAS mutant | non-Hodgkin lymphoma | resistant | Trametinib | Preclinical | Actionable | In a preclinical study, human non-Hodgkin lymphoma cells harboring mutant NRAS were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). | 26343583 |
NRAS mutant | lymphoma | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human lymphoma cells harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
NRAS mutant | lung adenocarcinoma | resistant | Trametinib | Preclinical | Actionable | In a preclinical study, human lung adenocarcinoma cell lines harboring mutant NRAS were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). | 26343583 |
NRAS mutant | transitional cell carcinoma | decreased response | Trametinib | Preclinical | Actionable | In a preclinical study, human urinary tract transitional cell carcinoma cells harboring mutant NRAS were moderately sensitive to Mekinist (trametinib) growth inhibition in culture (PMID: 26343583). | 26343583 |
NRAS mutant | acute myeloid leukemia | sensitive | LY3009120 | Preclinical | Actionable | In a preclinical study, LY3009120 inhibited proliferation of human NRAS mutant acute myeloid leukemia cell lines in culture (PMID: 26343583). | 26343583 |
NRAS mutant | sarcoma | resistant | Trametinib | Preclinical | Actionable | In a preclinical study, human sarcoma cells harboring mutant NRAS were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). | 26343583 |
NRAS mutant | acute myeloid leukemia | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human acute myeloid leukemia cell lines harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
NRAS mutant | multiple myeloma | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human multiple myeloma cells harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
NRAS mutant | melanoma | resistant | Vemurafenib | Preclinical | Actionable | In a preclinical study, human melanoma cell lines harboring a mutation in NRAS were resistant to Zelboraf (vemurafenib) mediated growth inhibition in culture (PMID: 26343583). | 26343583 |
NRAS mutant | liver cancer | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of liver cancer cell lines harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
NRAS Q61K | melanoma | sensitive | LY3009120 | Preclinical | Actionable | In a preclinical study, LY3009120 inhibited soft agar growth of human melanoma cancer cells harboring NRAS Q61K in culture (PMID: 26343583). | 26343583 |
NRAS Q61K | melanoma | resistant | Vemurafenib | Preclinical | Actionable | In a preclinical study, human melanoma cell lines harboring NRAS Q61K were insensitive to Zelboraf (vemurafenib) in culture (PMID: 26343583). | 26343583 |
NRAS Q61K | melanoma | sensitive | Selumetinib | Preclinical | Actionable | In a preclinical study, Selumetinib (AZD6244) inhibited proliferation of human melanoma cell lines harboring NRAS Q61K in culture (PMID: 26343583). | 26343583 |
NRAS Q61L | melanoma | decreased response | LY3009120 | Preclinical | Actionable | In a preclinical study, LY3009120 modestly inhibited soft agar growth of human melanoma cancer cells harboring NRAS Q61L in culture (PMID: 26343583). | 26343583 |
NRAS Q61L | melanoma | resistant | Vemurafenib | Preclinical | Actionable | In a preclinical study, human melanoma cells harboring NRAS Q61L were insensitive to Zelboraf (vemurafenib) in culture (PMID: 26343583). | 26343583 |
NRAS Q61L | melanoma | decreased response | Selumetinib | Preclinical | Actionable | In a preclinical study, Selumetinib (AZD6244) modestly inhibited proliferation of human melanoma cells harboring NRAS Q61L in culture (PMID: 26343583). | 26343583 |
TP53 D259Y | melanoma | sensitive | Selumetinib | Preclinical | Actionable | In a preclinical study, Selumetinib (AZD6244) inhibited proliferation of human melanoma cells harboring TP53 D259Y in culture (PMID: 26343583). | 26343583 |
TP53 D259Y | melanoma | sensitive | Vemurafenib | Preclinical | Actionable | In a preclinical study, Zelboraf (vemurafenib) inhibited proliferation of human melanoma cells TP53 D259Y in culture (PMID: 26343583). | 26343583 |
TP53 D259Y | melanoma | sensitive | LY3009120 | Preclinical | Actionable | In a preclinical study, LY3009120 modestly inhibited soft agar growth of human melanoma cancer cells harboring TP53 D259Y in culture (PMID: 26343583). | 26343583 |
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