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.
| Original language | English (US) |
|---|---|
| Article number | e147849 |
| Journal | Journal of Clinical Investigation |
| Volume | 131 |
| Issue number | 22 |
| DOIs | |
| State | Published - Nov 15 2021 |
Bibliographical note
Funding Information:We thank members of the Mouw lab for insights and discussion on all aspects of the work. We thank Dana-Farber Cancer Institute/ Harvard Cancer Center for the use of the Specialized Histopathology Core, which provided histology and immunohistochemistry services. Dana-Farber Cancer Institute/Harvard Cancer Center is supported in part by National Cancer Institute Cancer Center support grant NIH 5 P30 CA06516. Support was received from National Cancer Institute/NIH K08 CA219504 and Burroughs Wellcome Career Award for Medical Scientists (to KWM). We thank the Brigham and Women’s Hospital’s Cytogenomics Core Laboratory for assistance with RAF1 FISH experiments.
Funding Information:
Conflict of interest: J Bellmunt reports stock ownership of Rainier; honoraria from UpToDate; consulting/advising with Pierre Fabre, Astellas, Pfizer, Merck, Genentech (Roche), Novartis, AstraZeneca, MedImmune, and Bristol Myers Squibb; research funding from Millennium, Sanofi, Pfizer, and EMD Serono; and travel reimbursement from Pfizer, MSD Oncology, and Ipsen. DJK reports advising/consulting with Novartis, AADi, and Genentech (Roche) and research support from Genentech (Roche) and Revolution Medicines. GPS reports advising/ consulting with Bristol Myers Squibb, Genentech (Roche), EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, AstraZeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, and Immunomedics; research support from Sanofi, AstraZeneca, and Immunomedics; travel reimbursement from Bristol Myers Squibb and Astra-Zeneca; speaking fees from Physicians Education Resource, OncLive, Research to Practice, and Medscape; writing fees from UpToDate and Elsevier (editor of Practice Update Bladder Cancer Center of Excellence); and steering committee membership of trials/studies with Bristol Myers Squibb, Bavarian Nordic, Seattle Genetics, and QED (all unpaid) and AstraZeneca, EMD Serono, and Debiopharm (all paid). EMVA reports advising/consulting from Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, and Monte Rosa; research support from Novartis and Bristol Myers Squibb; equity in Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, and Monte Rosa; travel reimbursement from Genentech (Roche); and institutional patents filed on “Genomic biomarker of response to immunotherapy” (US Patent Application US20170115291A1) and “Methods, systems apparatus, and optimization for effective clinical analysis of cancer genomic data” (US Patent Application WO2015013191A1). KWM reports advising/consulting with Pfizer and EMD Serono and research support from Pfizer. Reference information: J Clin Invest. 2021;131(22):e147849. https://doi.org/10.1172/JCI147849. Submitted: February 3, 2021; Accepted: September 16, 2021; Published: November 15, 2021. Copyright: © 2021, American Society for Clinical Investigation.
Funding Information:
We thank members of the Mouw lab for insights and discussion on all aspects of the work. We thank Dana-Farber Cancer Institute/ Harvard Cancer Center for the use of the Specialized Histopathology Core, which provided histology and immunohistochemistry services. Dana-Farber Cancer Institute/Harvard Cancer Center is supported in part by National Cancer Institute Cancer Center support grant NIH 5 P30 CA06516. Support was received from National Cancer Institute/NIH K08 CA219504 and Burroughs Wellcome Career Award for Medical Scientists (to KWM). We thank the Brigham and Women?s Hospital?s Cytogenomics Core Laboratory for assistance with RAF1 FISH experiments.
Publisher Copyright:
Copyright: © 2021, American Society for Clinical Investigation.
