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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
STAT3 Inhibition Prevents Adaptive Resistance and Augments NK Cell Cytotoxicity to KRASG12C Inhibitors in Nonsmall
Zehao Pan1,2,3,4, Yuxian Qian1,2,3, Yajing Wang1,2,3,4,5
1Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, P. R. China.
Abstract:
KRASG12C inhibitors exhibit conspicuous clinical response in KRASG12C-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 KRASG12C inhibitor sotorasib in sensitive and resistant KRASG12C 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, KRASG12C 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 KRASG12C 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.
Insights
Combining KRAS G12C inhibitors with STAT3 inhibitors like napabucasin overcomes resistance in lung cancer. This strategy enhances tumor growth inhibition and boosts natural killer cell activity by targeting STAT3 and HLA-B.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- KRAS G12C inhibitors show promise in lung cancer but face adaptive resistance.
- Developing combination strategies is crucial to overcome therapeutic limitations.
Purpose of the Study:
- To identify compounds that synergize with KRAS G12C inhibitors to overcome resistance.
- To elucidate the mechanisms underlying adaptive resistance to KRAS G12C inhibitors.
Main Methods:
- High-throughput screening of a 423-compound library.
- Functional assays in KRAS G12C-mutant NSCLC cell lines.
- Analysis of tumor microenvironment, including NK cell infiltration and activation.
Main Results:
- Napabucasin, a STAT3 inhibitor, synergistically enhanced sotorasib's anti-tumor effect in sensitive and resistant NSCLC cells.
- Combined KRAS and STAT3 inhibition improved tumor growth inhibition and augmented NK cell activity.
- KRAS G12C inhibition led to compensatory STAT3 activation, which napabucasin abrogated, and identified STAT3 binding to the HLA-B promoter.
Conclusions:
- Co-targeting KRAS G12C and STAT3 overcomes adaptive resistance in NSCLC.
- This combination strategy enhances anti-tumor immunity by modulating NK cell activity via HLA-B.
- The study reveals a novel resistance mechanism involving STAT3-mediated upregulation of HLA-B to evade NK cell cytotoxicity.
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