2. Academic Validation
  3. Dual inhibition of HERs and PD-1 counteract resistance in KRASG12C-mutant head and neck cancer

Dual inhibition of HERs and PD-1 counteract resistance in KRASG12C-mutant head and neck cancer

  • J Exp Clin Cancer Res. 2024 Nov 20;43(1):308. doi: 10.1186/s13046-024-03227-0.
Ofra Novoplansky 1 2,  Sankar Jagadeeshan 1 2,  Manu Prasad 1 2,  Ksenia M Yegodayev 1 2,  Divyasree Marripati 1 2,  Raghda Abu Shareb 1 2,  Yariv Greenshpan 1 2,  Sooraj Mathukkada 1 2,  Talal Ben-Lulu 1 2,  Baisali Bhattacharya 1 2,  Angel Porgador 1 2,  Dexin Kong 3,  Johannes Brägelmann 4 5 6,  J Silvio Gutkind 7,  Moshe Elkabets 8 9
Affiliations

Affiliations

  • 1 The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, 84105, Beer-Sheva, Israel.
  • 2 Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • 3 School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin, China.
  • 4 Department of Translational Genomics, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50937, Cologne, Germany.
  • 5 Mildred Scheel School of Oncology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.
  • 6 University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, 50937, Cologne, Germany.
  • 7 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
  • 8 The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, 84105, Beer-Sheva, Israel. moshee@bgu.ac.il.
  • 9 Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. moshee@bgu.ac.il.
PMID: 39567998 DOI: 10.1186/s13046-024-03227-0
Abstract

Background: Basket clinical trials targeting the KRASG12C-mutation in solid tumors have shown initial promise, including in orphan KRASG12C head and neck Cancer (HNC). However, development of resistance to KRASG12C-mutant-specific inhibitors (KRASG12Ci) remains a major obstacle. Here, we investigated the intrinsic (tumor-cell autonomus) and tumor-microenvironment (TME) mechanisms of resistance to the KRASG12Ci-MRTX849 and AMG510 in a unique syngenic murine KRASG12C-mutated HNC cell line.

Methods: Western-blotting was used for protein abundance and activation, overexpression, and ligand activation studies to verify the intrinsic mechanism of resistance to KRASG12Ci in KRASG12C-mutated HNC cell line, 4NQO-L. In vitro KRASG12C-acquired-resistant cells were developed from 4NQO-L (4NQO-L-AcR). MRTX849/lapatinib combination efficacy, and CD8+ T-cells depletion, were assessed in C57BL/6 J mice and supplementation of anti-PD-1 (αPD-1) to MRTX849/lapatinib was also performed in 4NQO-L- KRASG12Ci-senisitve and 4NQO-L-AcR tumors. Immunohistochemistry (IHC) and Immunoflourescence (IF) analyses were performed to profile the TME and programmed death-ligand 1 (PD-L1) expression in tumors.

Results: Activation and upregulation of EGFR and HER2/3 (pan-HERs) are the intrinsic mechanism of resistance to KRASG12Ci in 4NQO-L cells, and blocking pan-HERs signaling with lapatinib enhanced MRTX849 efficacy in vitro by inhibiting the MAPK and Akt/mTOR pathways. 4NQO-L-AcR upregulated the expression of pan-HERs, and lapatinib treatment re-sensitized 4NQO-L-AcR to MRTX849. In mice, MRTX849 showed a slight anti-tumor effect, but in combination with lapatinib a significant tumor growth delay was observed, but all tumors progressed over time. Histopathology analysis of the TME revealed infiltration of CD8+ T-cells after treatment combination, and these CD8+ T-cells play a key role in MRTX849/lapatinib efficacy. MRTX849/lapatinib treatment upregulated PD-L1 overexpression in both stromal and tumor cells, which presumably suppressed CD8+ T-cells and enabled immune escape and tumor progression. Supplementation of αPD-1 prolonged the progression-free survival of 4NQO-L-bearing mice treated with MRTX849/lapatinib. MRTX849/lapatinib treatment delayed tumor growth of 4NQO-L-AcR in mice; however, the percentages of CD8+ T-cells in 4NQO-L-AcR were low, and supplementation of MRTX849/lapatinib with αPD-1 did not improve the outcome.

Conclusions: Our study highlights the critical need for blocking both intrinsic and extrinsic mechanisms of resistance for the prolonged response and shows that such treatment is ineffective in KRASG12Ci-AcR tumors.

Keywords

Adagrasib; Cell-autonomous; Drug resistance; HER signaling; Head and neck cancer; KRASG12C mutation; PD-L1/PD1; Sotorasib; Tumor microenvironment.

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