STAT3 Inhibition Prevents Adaptive Resistance and Augments NK Cell Cytotoxicity to KRAS(G12C) Inhibitors in Nonsmall Cell Lung Cancer.

KRAS(G12C) inhibitors exhibit conspicuous clinical response in KRAS(G12C)-mutant lung cancer, yet adaptive resistance, the rapid onset of intrinsic resistance, dampens their therapeutic success. Rational combination strategies could tackle this challenging problem. A high-throughput screening of a pharmacological library with 423 compounds revealed that napabucasin, a signal transducer and activator of transcription 3 (STAT3) inhibitor, synergistically potentiated the growth inhibition effect of the KRAS(G12C) inhibitor sotorasib in sensitive and resistant KRAS(G12C) NSCLC cell lines. Functional assays further revealed that the coordinated targeting of KRAS with STAT3 improved the inhibitory effect on tumor growth and augmented the infiltration and activation of natural killer (NK) cells within the tumor microenvironment. Mechanistically, KRAS(G12C) inhibition induced compensatory activation of STAT3, contingent on concomitant suppression of downstream ERK signaling, abrogated by napabucasin. Moreover, we unveiled and verified the binding site of phosphorylated STAT3 at the HLA-B promoter, an inhibitor ligand for NK cells. Our study dissected an unknown mechanism of adaptive resistance to KRAS(G12C) inhibitors, with the STAT3 activation sustaining the regrowth of tumor cells under KRAS inhibition and up-regulating HLA-B transcription to dampen the cytotoxicity of infiltrated NK cells.