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Abstract Recent genomic characterization studies have demonstrated the genetic heterogeneity of head and neck squamous cell carcinoma (HNSCC). Yet, most of these genetic aberrations remain undruggable. Anaplastic Lymphoma Kinase (ALK) is somatically mutated in ~3. 6% of HNSCC (18/504 cases, TCGA-HNSCC Firehose cohort, USA), and the majority of these ALK-mutated HNSCC cases are of advanced stage diseases. Here, we hypothesized that ALK mutations might plausibly contribute to HNSCC progression and could be potentially druggable. Unexpectedly, analysis of HNSCC genomic events revealed a novel co-occurrence relationship between ALK and PIK3CA genomic aberrations in TCGA-HNSCC Firehose cohort (Odds Ratio=2. 41; N=522 samples with CNV data), with subsequent validation in an independent metastatic MSK-MetTropism HNSCC cohort (Odds Ratio=5. 12; N=412). Consistent with this newly identified co-occurrence relationship, we showed that all 7 HNSCC-relevant ALK point mutations were potent drivers for HNSCC invasiveness and clonogenic growth only in corroboration with PIK3CA aberrations in HNSCC cell models, highlighting the functional importance of this novel ALK/PIK3CA cooperativity in HNSCC, likely reminiscent of ALK/MYCN cooperativity in neuroblastoma. Further, by clonogenic assay, we demonstrated pharmacologic vulnerabilities of all 7 ALK point mutations (including extracellular domain mutations) to ALK targeting by ceritinib in FaDu cell background with endogenous PIK3CA amplification. Strikingly, we were able to capture, for the first time, spontaneous emergence of a druggable ALK somatic mutation directly from a PIK3CA-altered HNSCC patient-derived culture (PDC) upon forced acquisition of anoikis-resistance ex vivo (PDC-25-AR), demonstrating co-evolution of ALK/PIK3CA aberrations in HNSCC likely associated with cancer progression. Patient-derived culture-xenograft (PDCx) of PDC-25-AR displayed remarkable sensitivity to ALK targeting, PI3K targeting, as well as their combination, with induction of apoptosis in these tumors compared to vehicle control. In conclusion, ALK aberrations corroborate with PIK3CA aberrations to promote HNSCC progression, yet, these events are potentially druggable in advanced HNSCC. Citation Format: Lan Wang, Helen Hoi-Yin Chan, Angel Yee Lok Fung, Yuen-Keng Ng, Patrick Kwok-Shing Ng, Yuxiong Su, Jason Ying Kuen Chan, Peony Hiu Yan Poon, Thomas Chun Kit Yeung, Chi Man Tsang, Hoi-Lam Ngan, Wenying Piao, Yuchen Liu, Jack Nimitz Smith, Tin Yu Samuel Law, Ee Ling Kong, Melissa Sue Ann Chan, Chun Ho Law, Sze-Man Chan, Zoey Wing Yee Liu, Joshua Chung-Hymn Ng, Gordon B. Mills, Vivian W. Y. Lui. Novel ALK/PIK3CA cooperativity in head and neck squamous cell carcinoma (HNSCC) progression 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 (7Suppl): Abstract nr LB414.
Wang et al. (Fri,) studied this question.