Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
The Journal of clinical investigation			2021 Sep 23		J Clin Invest

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 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	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 + 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
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 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 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 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
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
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	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