BRAF inhibition can promote progression of primary CLL cells independent of RAS mutation.

  • Major finding: BRAF inhibition can promote progression of primary CLL cells independent of RAS mutation.

  • Mechanism: Drug-bound BRAF and BCR–SYK signaling cooperatively induce paradoxical ERK activation in CLL cells.

  • Impact: Dual inhibition of BRAF and SYK reverses ERK activation and may suppress treatment-induced CLL.

Treatment with the BRAF inhibitor vemurafenib effectively suppresses ERK signaling and improves overall survival in patients with BRAF-mutant melanoma. Interestingly, BRAF inhibition can also induce other types of tumors, including cutaneous squamous lesions and chronic myelomonocytic leukemia, via paradoxical ERK activation in wild-type BRAF cells harboring RAS mutations. Yaktapour, Meiss, and colleagues report the case of a patient with metastatic BRAF-mutant melanoma who exhibited progression of preexisting chronic lymphocytic leukemia (CLL) in the absence of a RAS mutation during treatment with vemurafenib. Following vemurafenib discontinuation, the patient's CLL disease burden decreased. Analysis of patient-derived CLL cells revealed high levels of phosphorylated ERK in the presence of vemurafenib, indicative of BRAF inhibitor–mediated paradoxical ERK activation, which was reduced by the MEK inhibitor trametinib. In addition, vemurafenib treatment resulted in increased CLL cell proliferation and reduced survival of tumor-bearing mice in vivo. Sequencing confirmed that no genetic alterations that could be linked to aberrant RAS activity were present in these CLL cells, suggesting that activation of other signaling pathways drives CLL growth. Consistent with the role of chronic B-cell receptor (BCR) signaling in CLL, combined inhibition of spleen tyrosine kinase (SYK), which is required for BCR-mediated RAS activation, reversed BRAF inhibitor–driven paradoxical ERK activation and decreased RAS activity in vitro. Furthermore, SYK inhibition suppressed CLL growth and prevented vemurafenib-induced mortality in mice. These results were confirmed in primary CLL cells isolated from ten additional patients with CLL. Together, these data indicate that BCR signaling and vemurafenib-bound BRAF can cooperatively induce ERK activation in CLL cells in the absence of RAS mutations and suggest that dual inhibition of SYK and BRAF may limit treatment-induced CLL progression.

Yaktapour N, Meiss F, Mastroianni J, Zenz T, Andrlova H, Mathew NR, et al. BRAF inhibitor–associated ERK activation drives development of chronic lymphocytic leukemia. J Clin Invest 2014;124:5074–84.