Inhibition of ULK1/2 and KRAS controls tumor growth in preclinical models of lung cancer.
Phaedra C Ghazi, Kayla T O'Toole, Sanjana Srinivas Boggaram, Michael T Scherzer, Mark R Silvis, Yun Zhang, Madhumita Bogdan, Bryan D Smith, Guillermina Lozano, Daniel L Flynn, Eric L Snyder, Conan G Kinsey, Martin McMahon
Author Information
Phaedra C Ghazi: Department of Oncological Sciences, University of Utah, Salt Lake City, United States. ORCID
Kayla T O'Toole: Department of Oncological Sciences, University of Utah, Salt Lake City, United States.
Sanjana Srinivas Boggaram: Department of Oncological Sciences, University of Utah, Salt Lake City, United States.
Michael T Scherzer: Department of Oncological Sciences, University of Utah, Salt Lake City, United States.
Mark R Silvis: Department of Oncological Sciences, University of Utah, Salt Lake City, United States.
Yun Zhang: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, United States.
Madhumita Bogdan: Deciphera Pharmaceuticals, St. Lawrence, United States.
Bryan D Smith: Deciphera Pharmaceuticals, St. Lawrence, United States.
Guillermina Lozano: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, United States. ORCID
Daniel L Flynn: Deciphera Pharmaceuticals, St. Lawrence, United States.
Eric L Snyder: Department of Oncological Sciences, University of Utah, Salt Lake City, United States. ORCID
Conan G Kinsey: Department of Oncological Sciences, University of Utah, Salt Lake City, United States. ORCID
Martin McMahon: Department of Oncological Sciences, University of Utah, Salt Lake City, United States. ORCID
Mutational activation of occurs commonly in lung carcinogenesis and, with the recent U.S. Food and Drug Administration approval of covalent inhibitors of KRAS such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRAS-driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients who do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRAS, efforts are underway to develop effective combination therapies. Here, we report that the inhibition of KRAS signaling increases autophagy in KRAS-expressing lung cancer cells. Moreover, the combination of DCC-3116, a selective ULK1/2 inhibitor, plus sotorasib displays cooperative/synergistic suppression of human KRAS-driven lung cancer cell proliferation in vitro and superior tumor control in vivo. Additionally, in genetically engineered mouse models of KRAS-driven NSCLC, inhibition of either KRAS or ULK1/2 decreases tumor burden and increases mouse survival. Consequently, these data suggest that ULK1/2-mediated autophagy is a pharmacologically actionable cytoprotective stress response to inhibition of KRAS in lung cancer.
