
KRASG12C 신호 억제는 KRASG12C 발현 폐암 세포에서 자가포식을 증가시키며, KRASG12C와 ULK1/2 동시 억제는 체외 및 체내 모델에서 종양 성장을 억제한다.


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Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent FDA 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 that 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 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.

### Competing Interest Statement

Disclosures: Research described here was supported through a Sponsored Research Agreement between the University of Utah and Deciphera Pharmaceuticals and awarded to M.M and C.G.K. M.M has previously but no longer been retained as a paid consultant to Deciphera Pharmaceuticals; C.G.K reported personal fees from Deciphera Pharmaceuticals outside the submitted work. M.B and D.L.F are stockholders of Deciphera Pharmaceuticals. No other disclosures were reported.

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

krasg12c-억제와-ulk1-2-억제가-폐암-전임상-모델에서-종양-성장을-제어한다


KRASG12C 억제와 ULK1/2 억제가 폐암 전임상 모델에서 종양 성장을 제어한다
