Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	27	1	2015 Jan 12	85-96	Cancer Cell

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
CCT196969	CCT196969	6	0
CCT241161	CCT241161	5	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CCT196969		CCT-196969\|CCT 196969	LCK Inhibitor 6 RAF Inhibitor (Pan) 27 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) 27 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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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
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
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
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
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 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