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 Cancer cell
Vol 27
Issue 1
Date 2015 Jan 12
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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CCT196969 CCT196969 5 0
CCT241161 CCT241161 5 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CCT196969 RAF Inhibitor (Pan) 16 SRC Inhibitor 27 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 RAF Inhibitor (Pan) 16 SRC Inhibitor 27 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).
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
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 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
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
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 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 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 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
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 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