Blockade of RAF and autophagy is the one-two punch to take out Ras

Abstract

Activating mutations in RAS genes ( KRAS , HRAS , and NRAS ) are oncogenic drivers arising in about one-third of human malignancies (1, 2). Cancers with oncogenic RAS mutations are among those with the poorest prognosis, the most notorious example being pancreatic cancer with a 95% mutation frequency in KRAS and a 7% survival rate beyond 5 y of diagnosis. As such, targeting oncogenic RAS proteins or their functional output has been a longstanding priority for development of effective cancer therapies. Unfortunately, therapeutic targeting of oncogenic RAS proteins directly or of their individual downstream effector pathways has not been successful for the treatment of the vast majority of human cancers, suggesting that functional redundancies provide workarounds that sustain oncogenic activity. In PNAS, Lee et al. (3) use a novel combinatorial knockdown screening approach to identify essential RAS signaling and stress adaptation programs that, when cotargeted, compromise RAS-mediated cancer cell survival.\n\nRAS proteins are small GTPases that transduce signals from upstream growth factor receptors to downstream signaling pathways to stimulate growth, proliferation, and survival. In cancers, oncogenic mutations in RAS proteins such as KRAS G12V render them in the constitutively “on” position, decoupling regulatory growth signals from effector mechanisms. These unregulated growth signals drive the cancer phenotype through constitutive activation of the downstream RAF, RalGDS, and PI3K pathways (Fig. 1) (1, 2).\n\n\n\nFig. 1. \nEssential codependency of RAS-driven cancers on BRAF, CRAF, and autophagy. BRAF and CRAF provide key functional oncogenic signaling downstream of RAS that requires autophagy mediated by ATG7 to sustain survival. Coordinate blockade of BRAF, CRAF, and ATG7 provides the one-two punch and lethal blow to Ras-driven cancer cells.\n\n\n\nTargeting oncogenic RAS proteins directly has proved difficult, with the possible exception of the KRAS V12C mutation in a small subset of human cancers in which the cysteine residue … \n\n[↵][1]1Email: epwhite{at}cinj.rutgers.edu.\n\n [1]: #xref-corresp-1-1