biostudies-literatureNovoplansky OUnited States - Israel Binational Science FoundationIsrael Science FoundationNCI NIH HHS308https://www.ebi.ac.uk/biostudies/studies/S-EPMC11577641biostudies-literatureUnknown43(1)<h4>Background</h4>Basket clinical trials targeting the KRAS^G12C-mutation in solid tumors have shown initial promise, including in orphan KRAS^G12C head and neck cancer (HNC). However, development of resistance to KRAS^G12C-mutant-specific inhibitors (KRAS^G12Ci) remains a major obstacle. Here, we investigated the intrinsic (tumor-cell autonomus) and tumor-microenvironment (TME) mechanisms of resistance to the KRAS^G12Ci-MRTX849 and AMG510 in a unique syngenic murine KRAS^G12C-mutated HNC cell line.<h4>Methods</h4>Western-blotting was used for protein abundance and activation, overexpression, and ligand activation studies to verify the intrinsic mechanism of resistance to KRAS^G12Ci in KRAS^G12C-mutated HNC ceJournal of experimental & clinical cancer research : CRDual inhibition of HERs and PD-1 counteract resistance in KRAS&lt;sup&gt;G12C&lt;/sup&gt;-mutant head and neck cancer.PMC11577641#2021055BSFR01 CA247551700/16302/21ISFShareb RAPrasad MMarripati DElkabets MKong DGreenshpan YYegodayev KMMathukkada SNovoplansky OBen-Lulu TBhattacharya BBragelmann JPorgador AJagadeeshan SGutkind JSfalseDual inhibition of HERs and PD-1 counteract resistance in KRAS&lt;sup&gt;G12C&lt;/sup&gt;-mutant head and neck cancer.<h4>Background</h4>Basket clinical trials targeting the KRAS^G12C-mutation in solid tumors have shown initial promise, including in orphan KRAS^G12C head and neck cancer (HNC). However, development of resistance to KRAS^G12C-mutant-specific inhibitors (KRAS^G12Ci) remains a major obstacle. Here, we investigated the intrinsic (tumor-cell autonomus) and tumor-microenvironment (TME) mechanisms of resistance to the KRAS^G12Ci-MRTX849 and AMG510 in a unique syngenic murine KRAS^G12C-mutated HNC cell line.<h4>Methods</h4>Western-blotting was used for protein abundance and activation, overexpression, and ligand activation studies to verify the intrinsic mechanism of resistance to KRAS^G12Ci in KRAS^G12C-mutated HNC ce2024-01-01T00:00:00Z2024 Nov2026-06-02T04:33:10.429Z2025-04-04T23:32:17.321ZS-EPMC115776413956799810.1186/s13046-024-03227-0