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Tissue factor overexpression promotes resistance to KRAS-G12C inhibition in non-small cell lung cancer

Yu Zhang1, Liang Liu1, Jinpeng Pei1

  • 1Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.

Oncogene
|January 8, 2024
PubMed

Insights

Targeting tissue factor (TF) and the mTORC2 pathway can overcome resistance to KRASG12C inhibitors in non-small cell lung cancer (NSCLC). Combination therapies show synergistic effects, improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • KRASG12C inhibitors offer promise for non-small cell lung cancer (NSCLC) but face intrinsic and acquired resistance.
  • Tissue factor (TF) is overexpressed in KRAS-mutated NSCLC and linked to poor survival and suppressed anti-tumor immunity.
  • The TF/mTORC2 axis is implicated in resistance mechanisms to targeted therapies.

Purpose of the Study:

  • To investigate the role of tissue factor (TF) in KRASG12C-mutated NSCLC resistance to KRASG12C inhibitors.
  • To explore combination strategies involving TF-targeting agents and KRASG12C inhibitors.
  • To elucidate the mechanisms underlying TF-mediated resistance and immune evasion.

Main Methods:

  • Utilized HuSC1-39, a parent antibody of a TF-targeting antibody-drug conjugate (ADC).
  • Analyzed TF expression, signaling pathways (ERK, AKT, mTORC2), and immune cell infiltration in NSCLC patient tumors and cell lines.
  • Evaluated combination treatments (HuSC1-39 or MTI-31 with KRASG12C-I) in vitro and in an orthotopic lung tumor model.
  • Assessed effects on epithelial-mesenchymal transition (EMT) and macrophage polarization.

Main Results:

  • TF overexpression correlated with poor survival, elevated P-ERK/P-AKT, and low immune cell infiltration in KRAS-mutated NSCLC.
  • Resistant KRASG12C-NSCLC cells exhibited TF overexpression dependent on an mTORC2-mediated, proteasome-dependent pathway.
  • Combination therapy with HuSC1-39 or MTI-31 synergistically reduced tumor growth and sensitized KRASG12C-I response.
  • TF depletion diminished EMT, reduced tumor growth, and enhanced KRASG12C-I sensitivity.
  • TF-targeting agents modulated the tumor microenvironment, promoting M1-like macrophages with enhanced phagocytic capacity.

Conclusions:

  • The TF/mTORC2 axis is a novel mechanism driving immunosuppression and resistance to KRASG12C inhibitors in NSCLC.
  • Targeting this axis with HuSC1-39 or mTORC1/2 inhibitors can overcome resistance and improve therapeutic efficacy.
  • Combination strategies hold potential for enhancing treatment outcomes in KRAS-driven NSCLC.

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