Abstract 4741: Exploring possible drug resistance and sensitivity mechanisms in treatment-refracotry betel-nuts related HNSCC cell line(TW2.6) by whole exon sequencing and molecular signaling for future drug combinations
Authors: Chen Jo-Pai , Chang Jui-Ying , Hong Ruey-Long 
Published: September 2020

Abstract
Background: Betel nut chewing might contribute to (1)strong inflammation, angiogenesis, & invasion; (2)resistance to traditional therapies. Betel-nuts related HNSCC in Taiwan might belong to mesenchymal differentiation and have the worst prognosis. Our group found betel-nuts exposed HNSCC cell line, TW2.6, was resistant to traditional therapies. PDL1 western blotting was strong over TW2.6 with defective p53 mutation, p16 loss, and BCL2 overexpression. In our previous studies, Astragalus polysaccharides, PI3Kalpha inhibitor, AKT inhibitor, FGFR inhibitor, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, maybe through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and the modulation of stemness & PD1/PDL1 pathway. Afatinib & CDK4/6 inhibitors also have immuno-modulatory effects in our studies.
Purpose & Methods: NGS studies will be introduced to representative HNSCC cell lines to study molecular phenotypes of these HNSCC cell lines (including SCC4, SCC9, SCC15, SCC25, FaDu, KB, Cal27, SAS, & TW2.6) for future drug combinations & basic/translational research.
Results: TW2.6 had PIK3CA H1047R mutation, high TMB(8.42 muts/Mb)/MSS, and VEGF-A amplification. We found afatinib response on several cell lines not so correlated to EGFR expression & CNV status. Palbociclib response seemed to correlate to CCND1 gain and p16 loss; but FaDu had not so good palbociclib response even with these two changes and TW2.6 has good response even without these two. TW2.6 also had other genomic changes, such as HRAS & DDR2 mutations, FAT1 loss, amplification of FGF10/CCND3/SOX9, and deletions of STK11/ARID1B/TNFAIP3.
Conclusions: PI3K inhibitor, anti-angiogenesis therapies, and immunotherapy-containing regimens will be future combination options for betel-nuts related HNSCC by TW2.6 molecular signatures. Afatinib, CDK4/6 inhibitors, or DDR interventions could also enhance ICIs efficacy. The genomic landscapes of TW2.6 also deserve further studies about CDK4/6 inhibitor resistance, immunotherapy resistance, epigenetic modifications, novel targeted therapy, & biomarkers exploration.
Mutations in TW2.6TW2.6GenesN=1%TP531100%SPEN1100%FAT11100%MUC61100%BUB1B1100%EPHB11100%HRAS1100%PTPRD1100%ATM1100%CDK121100%CDK81100%DDR21100%GNAS1100%MYC1100%PDGFRB1100%PIK3CA1100%TNFSF111100%TSC21100%
Citation Format: Jo-Pai Chen, Jui-Ying Chang, Ruey-Long Hong. Exploring possible drug resistance and sensitivity mechanisms in treatment-refracotry betel-nuts related HNSCC cell line(TW2.6) by whole exon sequencing and molecular signaling for future drug combinations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4741.