Simultaneous Targeting of RAF, MEK, and ERK Limits Drug Resistance Free

BRAF mutations that hyperactivate ERK signaling are found in a subset of patients with a variety of tumor types. Targeting RAF alone or in combination with the downstream MEK kinase slows the growth BRAF-mutant tumors, but resistance eventually develops. ERK inhibitors (ERKi) have been developed to potentially treat these patients. Xue, Martelotto, and colleagues used single-cell DNA sequencing to track the evolution of resistance to ERKi in patient-derived xenograft (PDX) models of BRAF^V600E-driven lung cancer and melanoma. ERKi initially suppressed the growth of 3 of 6 lung cancer PDXs, but resistance emerged within several weeks. Single-cell copy-number analysis revealed high-level BRAF amplification in resistant PDXs that resulted in BRAF^V600E overexpression. BRAF amplification emerged independently in multiple subclones through parallel evolution and provided a growth advantage in the presence of ERKi. Thus, ERKi selected for BRAF-amplified cells, but intratumoral heterogeneity was maintained due to parallel evolutionary trajectories. When PDXs from patients treated with RAFi were subsequently treated with ERKi, a progressive increase in BRAF copy number occurred. Further, although treatment-naïve patients responded to ERKi, patients who had previously progressed on RAFi–MEKi combination therapy failed to respond to ERKi, altogether suggesting that sequential therapy may promote resistance due to selection for increased BRAF copy number. In contrast, combined treatment with RAFi, MEKi, and ERKi resulted in suppression of BRAF-amplified tumor growth, and tumors that regrew after treatment discontinuation did not exhibit increased BRAF copy number. Moreover, combined treatment on an intermittent schedule resulted in minimal toxicity and suppressed the growth of 11 of 11 lung cancer and melanoma PDXs. These findings suggest that concurrent targeting of RAF, MEK, and ERK may be more effective than sequential targeting in preventing the emergence of resistant BRAF-amplified subclones, supporting further investigation of this regimen in patients with BRAF-mutant tumors.

Xue Y, Martelotto L, Baslan T, Vides A, Solomon M, Mai TT, et al. An approach to suppress the evolution of resistance in BRAF^V600E-mutant cancer. Nat Med 2017;23:929–37.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.