Abstract 4408: CDK4/6 inhibitor(palbocilcib) efficacy for head and neck squamous cell carcinoma(HNSCC), including both HPV+ and HPV- cell lines
Authors: Chen Jo-Pai , Chang Jui-Ying , Hong Reuy-Long 
Published: August 2019

Background:

Betel nut chewing might contribute to (1)strong inflammation, angiogenesis, & invasion; (2)easy recurrence. Our group had found a betel-nuts exposed HNSCC cell line, TW2.6, was resistant to chemotherapies, radiation, and EGFR inhibitors. Defective p53 mutation, p16 loss, and BCL2 overexpression were seen in TW2.6. Astragalus polysaccharides, PI3Kalpha inhibitor, AKT inhibitor, FGFR inhibitor, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and the modulation of stemness & PD1/PDL1 pathway. TW2.6 might be similar to HPV- EMT subtype in TCGA. CDK4/6 inhibitor was proved to be effective in HPV-/pRB+ HNSCC and had strong immuno-modulatory effects. In our prior works, palbociclib could resensitize TW2.6 to docetaxel, afatinib, & radiation and enhance further response to BYL719 & foretinib(VEGFR2/c-MET/Axl triple inhibitor). Purpose and methods: To test palbociclib efficacy in HNSCC cell lines with different molecular phenotypes. SCC4, SCC9, SCC15, SCC25, FaDu, KB, Cal27, SAS, and TW2.6 evaluated for (1)in vitrosensitivity to palbociclib; (2)synergistic effect of palbociclib with other therapies by MTT assay, colony formation, flow cytometry, and western blotting.

Results:

Cell linesSCC25KBSASCAL27FaDuSCC15SCC9SCC4TW2.6Differ- entiationWellPoorPoorPoorPoorWellWellWellWell, but rapidly replicated, with high hyper-diploidy & complex rearrangementsHPV statusHPV 16/18HPV18--HPV 16/18--HPV 6/11-EGFR statusMediumLowHighHighMediumHighLowMedium to highUnknownDocetaxel sensitivity+++++++++++++ to +++++-+Cisplatin sensitivity+++++++++++++- to +-- to +5-FU sensitivity+++++++++++-+ to ++-- to +EGFR inhibitor sensitivity+++- to +-+++++ to +++++++++-Polo-like kinase Inhibitor sensitivity+++++++++++++ to +++- to +-- to +VEGFR2 Inhibitor sensitivity----+++++--++CDK4/6 Inhibitor response+++- to ++++++ to +++++++++++++ to +++Western blotsWeak p-AKT & VEGF-A, mild PDL1 and BMI-1, Gli-1(+)Weak p-AKT, mild PDL1 and strong VEGF-A & BMI-1, p16(+)Moderate p-AKT & BMI-1, high PDL1, mild VEGF-AHigh p-AKT & VEGF-A, mild PDL1 & BMI-1High VEGF-A, moderate p-AKT & PDL1, weak BMI-1, Gli-1(+)Weak p-AKT & VEGF-A, mild PDL1 & BMI-1Weak p-AKT, VEGF-A, & BMI-1, moderate PDL1Moderate p-AKT & VEGF-A, strong BMI-1, mild PDL1, Gli-1(+)High p-AKT, PDL1, & VEGF-A and moderate BMI-1OutcomesBest; like TCGA CL (HPV+) subtypeLike TCGA basal subtype, but responded to particular treatments eachBasalBasalLike TCGA mesen-chymal subtype (HPV+)Like TCGA CL(HPV-) subtype, different characters between these 3 cell linesCL(HPV-) subtypeCL(HPV-) subtypeWorse; like TCGA EMT subtype (HPV-)

Conclusion: Palbociclib had great efficacy over SCC15(classical HPV- type with EGFR overexpression) followed by SCC25, SAS, TW2.6, & CAL27; but little efficacy over KB. In HPV+ cell lines, palbociclib had promising response on SCC25(classical HPV+ type) and little response on FaDu(HPV+ mesenchymal type) & KB(basal type). SAS & CAL27, also basal types, responded well to palbocilclib. Further NGS analysis may translate these cell lines to represent TCGA subtypes for translational research.

Citation Format: Jo-Pai Chen, Jui-Ying Chang, Reuy-Long Hong. CDK4/6 inhibitor(palbocilcib) efficacy for head and neck squamous cell carcinoma(HNSCC), including both HPV+ and HPV- cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4408.