RAF1 Amplification Drives a Subset of Bladder Tumors and Confers Sensitivity to MAPK-Directed Therapeutics
This week we profile a recent publication in the Journal of Clinical Investigation from the lab of Dr. Kent Mouw
(pictured) at Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Beth Israel Deaconess Medical Center.
Can you provide a brief overview of your lab’s current research focus?
My lab studies the impact of alterations in DNA repair and cell signaling genes on tumor biology and therapy response with a particular interest in bladder cancer.
What is the significance of the findings in this publication?
In this work, we identify a subset of bladder tumors with amplification of RAF1 (CRAF). RAF1 amplifications are present in ~12% of bladder tumors but <2% of other tumor types. Using publicly available data as well as preclinical cell line and patiet-derived models, we show that RAF1-amplified bladder tumors are dependent on RAF1-mediated signaling for survival. Furthermore, we show that RAF1-amplified tumors are particularly sensitize to RAF dimerization inhibitors, an emerging class of RAF drugs. Finally, we show that tumors with activating HRAS or NRAS mutations (which are present in ~3% of bladder tumors but >10% of ureteral tumors) also have high levels of RAF1 activity and are sensitive to RAF dimerization inhibitors.
What are the next steps for this research?
We are interested in testing the clinical activity of RAF dimerization inhibitors in RAF1-amplified bladder tumors in the context of a clinical trial. We are also exploring rationale RAF inhibitor combination strategies. Finally, we are interested in understanding mechanisms of resistance to RAF inhibition in RAF1-amplified and HRAS/NRAS-mutant bladder tumors.
If you’d like us to mention your funding sources, please list them.
We acknowledge funding from the NCI and the Burroughs-Wellcome Fund.