Abstract LB413: A newly developed patient-derived culture panel identifies precision therapies and pan-effective agents for head and neck squamous cell carcinoma

Abstract Head and neck squamous carcinoma (HNSCC) is an aggressive cancer with few treatment options. Its well-known genetic heterogeneity presents a major challenge for precision medicine development. We report a newly developed panel of 20 HNSCC patient-derived cultures (HNSCC-PDCs) from advanced or recurrent HNSCC, with comprehensive somatic and germline characterization for precision medicine (PM) discovery. The PDCs retain genetic heterogeneity of the original patient tumors, and xenografts of which also phenocopied HNSCC patient tumors. Importantly, somatic and germline events that were never or seldom captured by long-established HNSCC cell lines are represented by the PDC panel, including HRAS-CASP8 co-mutations, EGFR-AS1 germline mutation, exonic germline PIK3CA mutation, sonic hedgehog (SHH) pathway and FGFR pathway mutations. We hypothesize that drug screening with this newly developed HNSCC-PDC panel that recapitulates HNSCC patient genetics may identify new gene-drug sensitivity relationships for precision medicine development in advanced HNSCC. Here, data from our pilot drug screen of 38 selected FDA approved/Phase I-II clinical trial agents first reveal: 1) HNSCC-PDC with the hotspot HRASp.G13R, together with CASP8p.L183S, is sensitive to tipifarnib vs. tipifarnib-resistance in a long-established HNSCC cell line, SNU899 with the same HRAS mutation. Subsequent high-content imaging cell death assay further demonstrates a dose-dependent tipifarnib-induced cell death in HRASp.G13R-mutated PDC, but not in SNU-899; 2) TP53-EP300 co-mutated HNSCC-PDCs are most sensitive to cisplatin with ~340 nM sensitivity (mean IC50) among all PDCs tested, which is 22 times more sensitive than that reported in Genomics of Drug Sensitivity in Cancer (GDSC) HNSCC cell lines; 3) EGFR-AS1 (c.2361G>A)-germline mutated PDCs, and MAPK1-mutated PDCs, are both hypersensitive to EGFR inhibitors (EGFRi: erlotinib and mobocertinib), which independently credentialed gene-drug sensitivity relationships reported in exceptional responders in HNSCC clinical trials. Further signaling investigation in PDC models demonstrates phospho-MAPK activation as a reliable surrogate biomarker for EGFRi sensitivity in HNSCC; 4) FRS3-mutated PDCs are sensitive to FDA-approved FGFR pathway inhibitors; and 5) TP53-wildtype HNSCC-PDCs are 150-fold more sensitive to novel p53-MDM2 interaction inhibitors vs. TP53-mutated PDCs, a phenomenon that cannot be captured in long-established TP53-wildtype HNSCC cell lines. Lastly, 4 pan-PDC effective agents are identified with nM sensitivities and high drug activities (i.e. drug-induced growth inhibition) in more than half of our PDC models. These include 3 FDA-approved agents, TAK-981, Selinexor (a novel XPO1 inhibitor), and trametinib, as well as the preclinical agent JQ1. In conclusion, our pilot HNSCC-PDC drug screen identifies new gene-drug sensitivity relationships for HNSCC PM development and new pan-effective agents for advanced HNSCC. Citation Format: Yuen Keng Ng, Hui Li, Wenying Piao, Cecilia Pik Yuk Lau, Peony Hiu Yan Poon, Tin Yu Samuel Law, Jason Ying Kuen Chan, Yuxiong Su, Chin Wang Lau, Zigui Chen, Laura Ren Huey Ip, Thomas Chung-Kit Yeung, Sai Fung Yeung, Jason Hoi-Lam Ngan, Zoey Wing Yee Liu, Noah R. Wiese, Vivie Vo, Zoey Patel, Jeremia Onyekachi, Laili Afzali, Jasmine Zohal Afzali, Jack Nimitz Smith, Vivian Wai Yan Lui. A newly developed patient-derived culture panel identifies precision therapies and pan-effective agents for head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB413.