BRAF-Like Colorectal Cancer Cells Are Selectively Dependent on RANBP2

Approximately 8% to 10% of patients with colorectal cancer harbor a BRAF^V600E mutation that is associated with poor outcome and chemotherapeutic resistance. These tumors display a distinct gene expression signature that is also observed in colorectal cancers lacking the BRAF^V600E mutation, which are collectively referred to as BRAF-like and represent approximately 20% of colorectal cancers. To identify specific vulnerabilities of BRAF-like colorectal cancer cells, Vecchione, Gambino, and colleagues performed a loss-of-function synthetic lethal screen and found that the small GTP-binding protein RANBP2 was selectively lethal in these cells. Suppression of RANBP2, which has been linked to kinetochore function, led to a significant mitotic delay, mitotic defects, and apoptosis in BRAF-like colorectal cancer cells but not non–BRAF-like colorectal cancer cells. Microtubule outgrowth from kinetochores, but not from centrosomes, was impaired in BRAF-like colorectal cancer cells, suggesting a potential explanation for their dependency on RANBP2. Hypothesizing that BRAF-like colorectal cancer cells would be sensitive to microtubule inhibitors, the authors analyzed a large drug-sensitivity dataset and observed that BRAF-like colorectal cancer cells were significantly more sensitive to the mitotic spindle poison vinorelbine compared with non–BRAF-like colorectal cancer cells, due to prolonged mitotic arrest. Moreover, intrinsic sensitivity to the antibody–drug conjugate DM4, which blocks tubulin polymerization, correlated with BRAF^V600E mutation in colorectal cancer patient-derived xenograft models, further supporting the idea that BRAF^V600E mutations target microtubule dynamics. In support of the concept that BRAF-like colorectal cancers are sensitive to mitotic spindle poisons, a BRAF-like expression profile was observed in the tumor tissue of an exceptional responder in a clinical trial of a vinorelbine-related compound in CRC. Together, these results demonstrate that RANBP2-dependent microtubule defects in BRAF-like cancer cells may be therapeutically exploited and suggest that vinorelbine or other microtubule inhibitors may have clinical benefit in BRAF-like colorectal cancer.

Vecchione L, Gambino V, Raaijmakers J, Schlicker A, Fumagalli A, Russo M, et al. A vulnerability of a subset of colon cancers with potential clinical utility. Cell 2016;165:317–30.