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000306283 005__ 20251119104046.0
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000306283 041__ $$aEnglish
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000306283 1001_ $$aNovoplansky, Ofra$$b0
000306283 245__ $$aDual inhibition of HERs and PD-1 counteract resistance in KRASG12C-mutant head and neck cancer.
000306283 260__ $$aHeidelberg$$bSpringer$$c2024
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000306283 520__ $$aBasket 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.
000306283 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
000306283 650_7 $$2Other$$aAdagrasib
000306283 650_7 $$2Other$$aCell-autonomous
000306283 650_7 $$2Other$$aDrug resistance
000306283 650_7 $$2Other$$aHER signaling
000306283 650_7 $$2Other$$aHead and neck cancer
000306283 650_7 $$2Other$$aKRASG12C mutation
000306283 650_7 $$2Other$$aPD-L1/PD1
000306283 650_7 $$2Other$$aSotorasib
000306283 650_7 $$2Other$$aTumor microenvironment
000306283 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$aProto-Oncogene Proteins p21(ras)
000306283 650_7 $$2NLM Chemicals$$aProgrammed Cell Death 1 Receptor
000306283 650_7 $$2NLM Chemicals$$aKRAS protein, human
000306283 650_2 $$2MeSH$$aMice
000306283 650_2 $$2MeSH$$aAnimals
000306283 650_2 $$2MeSH$$aHead and Neck Neoplasms: drug therapy
000306283 650_2 $$2MeSH$$aHead and Neck Neoplasms: genetics
000306283 650_2 $$2MeSH$$aHead and Neck Neoplasms: pathology
000306283 650_2 $$2MeSH$$aHead and Neck Neoplasms: metabolism
000306283 650_2 $$2MeSH$$aProto-Oncogene Proteins p21(ras): genetics
000306283 650_2 $$2MeSH$$aProto-Oncogene Proteins p21(ras): metabolism
000306283 650_2 $$2MeSH$$aHumans
000306283 650_2 $$2MeSH$$aDrug Resistance, Neoplasm
000306283 650_2 $$2MeSH$$aMutation
000306283 650_2 $$2MeSH$$aProgrammed Cell Death 1 Receptor: antagonists & inhibitors
000306283 650_2 $$2MeSH$$aProgrammed Cell Death 1 Receptor: metabolism
000306283 650_2 $$2MeSH$$aCell Line, Tumor
000306283 7001_ $$aJagadeeshan, Sankar$$b1
000306283 7001_ $$aPrasad, Manu$$b2
000306283 7001_ $$aYegodayev, Ksenia M$$b3
000306283 7001_ $$aMarripati, Divyasree$$b4
000306283 7001_ $$aShareb, Raghda Abu$$b5
000306283 7001_ $$aGreenshpan, Yariv$$b6
000306283 7001_ $$aMathukkada, Sooraj$$b7
000306283 7001_ $$aBen-Lulu, Talal$$b8
000306283 7001_ $$aBhattacharya, Baisali$$b9
000306283 7001_ $$aPorgador, Angel$$b10
000306283 7001_ $$aKong, Dexin$$b11
000306283 7001_ $$aBrägelmann, Johannes$$b12
000306283 7001_ $$aGutkind, J Silvio$$b13
000306283 7001_ $$00000-0003-3634-9098$$aElkabets, Moshe$$b14
000306283 773__ $$0PERI:(DE-600)2430698-8$$a10.1186/s13046-024-03227-0$$gVol. 43, no. 1, p. 308$$n1$$p308$$tJournal of experimental & clinical cancer research$$v43$$x0392-9078$$y2024
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