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@ARTICLE{Novoplansky:306283,
      author       = {O. Novoplansky and S. Jagadeeshan and M. Prasad and K. M.
                      Yegodayev and D. Marripati and R. A. Shareb and Y.
                      Greenshpan and S. Mathukkada and T. Ben-Lulu and B.
                      Bhattacharya and A. Porgador and D. Kong and J. Brägelmann
                      and J. S. Gutkind and M. Elkabets},
      title        = {{D}ual inhibition of {HER}s and {PD}-1 counteract
                      resistance in {KRASG}12{C}-mutant head and neck cancer.},
      journal      = {Journal of experimental $\&$ clinical cancer research},
      volume       = {43},
      number       = {1},
      issn         = {0392-9078},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2025-02509},
      pages        = {308},
      year         = {2024},
      note         = {#DKFZ-MOST-Ca222#},
      abstract     = {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.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.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.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     = {Mice / Animals / Head and Neck Neoplasms: drug therapy /
                      Head and Neck Neoplasms: genetics / Head and Neck Neoplasms:
                      pathology / Head and Neck Neoplasms: metabolism /
                      Proto-Oncogene Proteins p21(ras): genetics / Proto-Oncogene
                      Proteins p21(ras): metabolism / Humans / Drug Resistance,
                      Neoplasm / Mutation / Programmed Cell Death 1 Receptor:
                      antagonists $\&$ inhibitors / Programmed Cell Death 1
                      Receptor: metabolism / Cell Line, Tumor / Adagrasib (Other)
                      / Cell-autonomous (Other) / Drug resistance (Other) / HER
                      signaling (Other) / Head and neck cancer (Other) / KRASG12C
                      mutation (Other) / PD-L1/PD1 (Other) / Sotorasib (Other) /
                      Tumor microenvironment (Other) / Proto-Oncogene Proteins
                      p21(ras) (NLM Chemicals) / Programmed Cell Death 1 Receptor
                      (NLM Chemicals) / KRAS protein, human (NLM Chemicals)},
      ddc          = {610},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39567998},
      pmc          = {pmc:PMC11577641},
      doi          = {10.1186/s13046-024-03227-0},
      url          = {https://inrepo02.dkfz.de/record/306283},
}