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Ref Type Journal Article
PMID (34554931)
Authors Bekele RT, Samant AS, Nassar AH, So J, Garcia EP, Curran CR, Hwang JH, Mayhew DL, Nag A, Thorner AR, Börcsök J, Sztupinszki Z, Pan CX, Bellmunt J, Kwiatkowski DJ, Sonpavde GP, Van Allen EM, Mouw KW
Title RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics.
Journal The Journal of clinical investigation
Vol
Issue
Date 2021 Sep 23
URL
Abstract Text Bladder cancer is a genetically heterogeneous disease and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient-derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS or NRAS activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a novel dependency in a subset comprising nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rationale therapeutic strategy.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
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
NRAS Q61R urinary bladder cancer sensitive Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, Mekinist (trametinib) treatment decreased tumor weight of a cell line xenograft model of bladder cancer harboring NRAS Q61R (PMID: 34554931). 34554931
NRAS Q61R urinary bladder cancer sensitive LXH 254 Preclinical - Cell line xenograft Actionable In a preclinical study, LXH 254 treatment decreased Mek signaling, colony formation and viability, and increased apoptosis in a bladder cancer cell line harboring NRAS Q61R in culture and decreased tumor weight and volume in a cell line xenograft model (PMID: 34554931). 34554931
NRAS Q61R urinary bladder cancer sensitive RAF265 Preclinical - Cell culture Actionable In a preclinical study, RAF265 treatment decreased viability of a bladder cancer cell line harboring NRAS Q61R in culture (PMID: 34554931). 34554931
HRAS G12V urinary bladder cancer sensitive RAF265 Preclinical - Cell culture Actionable In a preclinical study, RAF265 treatment decreased viability and colony formation of a bladder cancer cell line harboring HRAS G12V in culture (PMID: 34554931). 34554931
HRAS G12V urinary bladder cancer sensitive RAF265 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, RAF265 and Mekinist (trametinib) combination treatment inhibited colony formation compared to RAF265 alone in cultured cells harboring HRAS G12V (PMID: 34554931). 34554931
NRAS Q61R urinary bladder cancer sensitive RAF265 + Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, RAF265 and Mekinist (trametinib) combination treatment decreased Erk1/2 phosphorylation in cultured cells and decreased tumor volume and weight of a cell line xenograft model harboring NRAS Q61R (PMID: 34554931). 34554931
HRAS G12V urinary bladder cancer sensitive LXH 254 Preclinical - Cell culture Actionable In a preclinical study, LXH 254 treatment decreased viability of a bladder cancer cell line harboring HRAS G12V in culture (PMID: 34554931). 34554931
NRAS Q61L urinary bladder cancer sensitive RAF265 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, RAF265 and Mekinist (trametinib) combination treatment inhibited colony formation compared to RAF265 alone in cultured cells harboring NRAS Q61L (PMID: 34554931). 34554931
NRAS Q61R urinary bladder cancer sensitive LXH 254 + Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, LXH 254 and Mekinist (trametinib) combination treatment decreased tumor volume and weight compared to vehicle in a cell line xenograft model of bladder cancer harboring NRAS Q61R (PMID: 34554931). 34554931
NRAS Q61L urinary bladder cancer sensitive RAF265 Preclinical - Cell culture Actionable In a preclinical study, RAF265 treatment decreased colony formation of a bladder cancer cell line harboring NRAS Q61L in culture (PMID: 34554931). 34554931