Author response: Inhibition of ULK1/2 and KRASG12C controls tumor growth in preclinical models of lung cancer
Year: 2024
Type: peer-review
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 KRAS G12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC).However, not all KRAS G12C -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 G12C , efforts are underway to develop effective combination therapies.Here, we report that the inhibition of KRAS G12C signaling increases autophagy in KRAS G12C -expressing lung cancer cells.Moreover, the combination of DCC-3116, a selective ULK1/2 inhibitor, plus sotorasib displays cooperative/synergistic suppression of human KRAS G12C -driven lung cancer cell proliferation in vitro and superior tumor control in vivo.Additionally, in genetically engineered mouse models of KRAS G12C -driven NSCLC, inhibition of either KRAS G12C 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 G12C in lung cancer. eLife assessmentThis is a mechanistic study showing the effect of combining inhibition of autophagy (through ULK1/2) and KRAS (using sotorasib) on KRAS mutant NSCLC making the study valuable to cancer biologists and more broadly in a clinical setting.The evidence generated by GEM mouse models and cell lines is solid but could be further strengthened by increasing the mouse cohort size.This study holds translational relevance beyond NSCLC to other indications that carry KRAS mutations.
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Awards: G1216882433, G1620451807, G1829687038, G2072210443, G3634115697, G3636875265, G3669389645, Role of p53 Missense Mutations on Tumorigenesis in Vivo, G4264322999, G4355517036, G5197853449, G5993569499, G6717222331, G7181130355, Resistance Mechanisms to Combined Trametinib and 4-aminoquinolones in the Inhibition of Pancreatic Cancer, G858682239, G9000048739, G9000130100, G9000153296
OpenAlex ID: W4402138241