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Ref Type | Journal Article | ||||||||||||
PMID | (25500121) | ||||||||||||
Authors | Girotti MR, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, Whittaker S, Saturno G, Viros A, Pedersen M, Suijkerbuijk BM, Menard D, McLeary R, Johnson L, Fish L, Ejiama S, Sanchez-Laorden B, Hohloch J, Carragher N, Macleod K, Ashton G, Marusiak AA, Fusi A, Brognard J, Frame M, Lorigan P, Marais R, Springer C | ||||||||||||
Title | Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma. | ||||||||||||
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Abstract Text | BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance. |
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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CCT196969 | CCT196969 | 6 | 0 |
CCT241161 | CCT241161 | 5 | 0 |
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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CCT196969 | CCT-196969|CCT 196969 | LCK Inhibitor 6 RAF Inhibitor (Pan) 28 SRC Inhibitor 31 | CCT196969 is a paradox-breaking pan-RAF inhibitor, with additional activity against SRC and LCK, which potentially results in decreased growth of tumor cells, including cells resistant to BRAF inhibitors (PMID: 25500121). | |
CCT241161 | LCK Inhibitor 6 RAF Inhibitor (Pan) 28 SRC Inhibitor 31 | CCT241161 is a paradox-breaking pan-RAF inhibitor, with additional activity against SRC and LCK, which potentially results in decreased growth of tumors, including those resistant to BRAF inhibitors (PMID: 25500121). |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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NRAS mutant | melanoma | sensitive | CCT241161 | Preclinical | Actionable | In a preclinical study, CCT241161 inhibited growth of melanoma cells harboring NRAS mutations in culture (PMID: 25500121). | 25500121 |
BRAF V600D | melanoma | sensitive | CCT241161 | Preclinical | Actionable | In a preclinical study, CCT241161 inhibited MEK and ERK phosphorylation and growth of melanoma cells harboring BRAF V600D in culture (PMID: 25500121, PMID: 17210691). | 25500121 17210691 |
NRAS mutant | melanoma | sensitive | CCT196969 | Preclinical | Actionable | In a preclinical study, CCT196969 inhibited growth of melanoma cells harboring NRAS mutations in culture (PMID: 25500121). | 25500121 |
BRAF V600E | colorectal cancer | sensitive | CCT241161 | Preclinical | Actionable | In a preclinical study, CCT241161 inhibited growth of colorectal cancer cell lines harboring BRAF V600E in culture (PMID: 25500121, PMID: 15294323). | 25500121 15294323 |
NRAS Q61L | melanoma | sensitive | CCT241161 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, CCT241161 inhibited MEK and ERK activation and growth of a melanoma cell line harboring NRAS Q61L in culture, and inhibited tumor growth in a NRAS Q61L-mutant melanoma cell line xenograft model (PMID: 25500121, PMID: 23431193). | 25500121 23431193 |
BRAF V600E | melanoma | sensitive | CCT196969 | Preclinical - Pdx | Actionable | In a preclinical study, CCT196969 inhibited growth of a human melanoma cell line harboring BRAF V600E in culture, and induced tumor regression in several BRAF V600E-mutant melanoma patient-derived xenograft models (PMID: 25500121). | 25500121 |
BRAF V600D | melanoma | sensitive | CCT196969 | Preclinical | Actionable | In a preclinical study, CCT196969 inhibited MEK and ERK phosphorylation and growth of melanoma cells harboring BRAF V600D in culture (PMID: 25500121, PMID: 17210691). | 25500121 17210691 |
BRAF V600E | colorectal cancer | sensitive | CCT196969 | Preclinical - Cell culture | Actionable | In a preclinical study, CCT196969 inhibited growth of BRAF-mutant colorectal cancer cell lines in culture (PMID: 25500121), which have been reported to harbor BRAF V600E (PMID: 15294323). | 25500121 15294323 |
NRAS Q61L | melanoma | sensitive | CCT196969 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, CCT196969 inhibited MEK and ERK activation and growth of a melanoma cell line harboring NRAS Q61L in culture, and inhibited tumor growth in a NRAS Q61L-mutant melanoma cell line xenograft model (PMID: 25500121, PMID: 23431193). | 25500121 23431193 |
NRAS Q61L | melanoma | resistant | PLX4720 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, PLX4720 did not inhibit growth of melanoma cells harboring NRAS Q61L in culture or in cell line xenograft models (PMID: 25500121, PMID: 23431193). | 25500121 23431193 |
BRAF V600E | melanoma | sensitive | CCT241161 | Preclinical - Pdx | Actionable | In a preclinical study, CCT241161 inhibited growth of a human melanoma cell line harboring BRAF V600E in culture, and induced tumor regression in several BRAF V600E-mutant melanoma patient-derived xenograft models (PMID: 25500121). | 25500121 |