Inhibition of ULK1/2 and KRASG12C controls tumor growth in preclinical models of lung cancer

Author:

Ghazi Phaedra C12ORCID,O'Toole Kayla T12,Srinivas Boggaram Sanjana12,Scherzer Michael T12,Silvis Mark R12,Zhang Yun3,Bogdan Madhumita4,Smith Bryan D4,Lozano Guillermina3ORCID,Flynn Daniel L4,Snyder Eric L125ORCID,Kinsey Conan G126ORCID,McMahon Martin127ORCID

Affiliation:

1. Department of Oncological Sciences, University of Utah

2. Huntsman Cancer Institute, University of Utah

3. Department of Genetics, The University of Texas MD Anderson Cancer Center

4. Deciphera Pharmaceuticals

5. Department of Pathology, University of Utah

6. Department of Internal Medicine, Division of Medical Oncology, University of Utah

7. Department of Dermatology, University of Utah

Abstract

Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent U.S. Food and Drug Administration approval of covalent inhibitors of KRASG12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRASG12C-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 KRASG12C, efforts are underway to develop effective combination therapies. Here, we report that the inhibition of KRASG12C signaling increases autophagy in KRASG12C-expressing lung cancer cells. Moreover, the combination of DCC-3116, a selective ULK1/2 inhibitor, plus sotorasib displays cooperative/synergistic suppression of human KRASG12C-driven lung cancer cell proliferation in vitro and superior tumor control in vivo. Additionally, in genetically engineered mouse models of KRASG12C-driven NSCLC, inhibition of either KRASG12C 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 KRASG12C in lung cancer.

Funder

National Cancer Institute

Huntsman Cancer Foundation

Huntsman Cancer Institute, University of Utah

V Foundation for Cancer Research

Publisher

eLife Sciences Publications, Ltd

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