RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics
Raie T. Bekele, Amruta S. Samant, Amin H. Nassar, Jonathan So, Elizabeth P. Garcia, Catherine R. Curran, Justin H. Hwang, David L. Mayhew, Anwesha Nag, Aaron R. Thorner, Judit Börcsök, Zsofia Sztupinszki, Chong-Xian Pan, Joaquim Bellmunt, David J. Kwiatkowski, Guru P. Sonpavde, Eliezer M. Van Allen, Kent W. Mouw
Raie T. Bekele, Amruta S. Samant, Amin H. Nassar, Jonathan So, Elizabeth P. Garcia, Catherine R. Curran, Justin H. Hwang, David L. Mayhew, Anwesha Nag, Aaron R. Thorner, Judit Börcsök, Zsofia Sztupinszki, Chong-Xian Pan, Joaquim Bellmunt, David J. Kwiatkowski, Guru P. Sonpavde, Eliezer M. Van Allen, Kent W. Mouw
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Research Article Oncology

RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics

Abstract

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 dependency in a subset making up nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rational therapeutic strategy.

Authors

Raie T. Bekele, Amruta S. Samant, Amin H. Nassar, Jonathan So, Elizabeth P. Garcia, Catherine R. Curran, Justin H. Hwang, David L. Mayhew, Anwesha Nag, Aaron R. Thorner, Judit Börcsök, Zsofia Sztupinszki, Chong-Xian Pan, Joaquim Bellmunt, David J. Kwiatkowski, Guru P. Sonpavde, Eliezer M. Van Allen, Kent W. Mouw

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Figure 6

A RAF1-amplified PDX is sensitive to RAF plus MEK inhibition.

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A RAF1-amplified PDX is sensitive to RAF plus MEK inhibition. (A) H&...
(A) H&E and IHC staining for RAF1, the luminal differentiation marker GATA3, and the basal differentiation marker CK5 in a RAF1-amplified PDX tumor show strong RAF1 staining in tumor cells as well as GATA3 staining consistent with a luminal phenotype. Original magnification, ×20 ((H&E, GATA3 and CK5); ×40 (RAF1). (B) Tumor volume measurements for RAF1-amplified PDX-bearing mice randomized to RAF265 plus trametinib versus no treatment. Significant differences in average tumor size between treated and untreated arms are denoted with asterisks.*P < 0.05; **P < 0.005; ***P < 0.0005, unpaired 2-tailed Student’s t test. (C) Kaplan-Meier survival curves showing percentage of surviving mice in the RAF265 plus trametinib versus untreated arms. Asterisks denote statistical significance by log-rank (Mantel-Cox) test. (D) Photographs of excised tumors from all mice in both arms. (E) The average end-of-experiment tumor weight was significantly lower in the RAF265 plus trametinib–treated mice compared with the untreated mice. Asterisks denote statistical significance by unpaired 2-tailed Student’s t test.