Abstract The intrinsic ability of cancer cells to evade death underpins tumorigenesis, progression, metastasis and the survival of drug-tolerant persister (DTP) cells. Herein, we discovered that when activated, the small GTPase ARF6 plays a central role in tumor survival by facilitating expression of the BRAFV600E oncoprotein. Tumor-specific Arf6 deletion caused a significant reduction in BRAFV600E protein and MAPK signaling and prevented rapid tumor progression. In the context of targeted therapy, BRAF inhibition induced swift activation of ARF6, driving a positive feedback loop that restored MAPK-driven anti-apoptotic signaling, facilitated DTP cell survival during the early phases of treatment and contributed to drug-tolerant growth. In patient-derived melanoma cells with innate or clinically acquired resistance to MAPK inhibitors, ARF6 inhibition enhanced sensitivity to combined BRAF + MEK inhibition. Collectively, these findings elucidate an ARF6-dependent mechanism of BRAF oncoprotein synthesis that may be exploited in BRAFV600E driven cancers as a therapeutic vulnerability.
Grossmann et al. (Wed,) studied this question.