Targeting MEK1/2 inhibitor resistance in RAS-mutated cancers.

Although the RAF\u003eMEK\u003eERK MAP kinase pathway is key to the development of many RAS-mutated cancers, efforts to target this pathway with pharmacologic inhibitors have failed to deliver clinical benefit to patients. Here we show that inhibition of RAS\u003eRAF\u003eMEK\u003eERK signaling in RAS-mutated cancer cell lines elicits autophagy, a process of cellular recycling that protects cancer cells from the potentially cytotoxic effects of RAF\u003eMEK\u003eERK pathway inhibition. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic antiproliferative effects against cell lines in vitro and promotes regression of xenografted patient-derived tumors in mice. Finally, treatment of a cancer patient with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking, disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven malignancies such as melanoma, lung, and pancreatic cancer. Citation Format: Conan Kinsey, Soledad Camolotto, Amelie Boespflug, Katrin Gullien, Amanda Truong, Mona Foth, Jill Shea, Michael Seipp, Jeffrey Yap, Lance Burrell, David Lum, Jonathan Whisenant, Courtney Cavalier, Kaitren Rehbein, Stephanie Cutler, Kajsa Afotler, Alana Welm, Bryan Welm, Courtney Scaife, Eric Snyder, Martin McMahon. Targeting MEK1/2 inhibitor resistance in RAS-mutated cancers [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA25.