381P - Novel treatments for betel-nut related HNSCC in Taiwan

Abstract

Background

The treatment of HNSCC in Taiwan is still challenging. Betel-nut chewing might contribute to (1)strong inflammation, invasion, and angiogenesis; (2) poor response to all treatments. We try to prove the difference of betel-nut related HNSCC in several aspects reflecting clinical obstacles of HNSCC in Taiwan and design novel treatments.

Methods

HNSCC cell lines (SCC4/9/15/25, FaDu, KB, Cal27, SAS, and TW2.6, betel-nut related) were used to evaluate (1) in vitro drug sensitivity; (2) synergistic effect of target therapies and irradiation with MTT, colony formation assay, flow cytometry, and western blotting; (3) invasion capacity by wound healing; (4) synergistic effect with chemotherapy, EGFR inhibitor, and polo-like kinase inhibitor. TW2.6 had already been proved to possess defective p53, p16 loss, and increased Bcl2.

Results

The MTT showed TW2.6 was resistant to all treatments. TW2.6 was sensitive to PI3K/mTOR dual inhibition(BEZ235); and polo-like kinase inhibitor(volasertib) combined with radiation, resulting in significant G2/M arrest in flow-cytometry and increased cyclin B levels & apoptosis in western blotting. Nintedanib & regorafenib(VEGFR/PDGFR/FGFR triple inhibitor) and foretinib (VEGFR/c-MET/Axl triple inhibitor) were found to suppress HUVEC, block invasion capacity of TW2.6, inhibit the growth of TW2.6, and resensitize TW2.6 to respond to chemotherapy, EGFR inhibitor, and polo-like kinase inhibitor. Western blotting showed (1)mesenchymal differentiation(Slug, Snail, Axl, c-MET, Twist, Vimentin, Claudin-1), stemness marker(BMI-1), and PI3K/Akt/mTOR signaling(p-Akt and p70S6K) decreased after nintedanib, regorafenib, and foretinib; (2)PDL1 drop after foretinib use. Besides, TW2.6 was also sensitive to CDK4/6 inhibitor(palbociclib), Bcl2 inhibitor(ABT-199), and especially ALK inhibitor(ceritinib).

Conclusions

TW2.6 might reflect treatment refractoriness of betel-nut related HNSCC in Taiwan. PI3K/mTOR dual inhibition, polo-like kinase inhibitor with radiation, VEGFR2/FGFR/PDGFR or VEGFR2/c-MET/Axl triple blockage, and novel interventions, such as CDK4/6, Bcl2, and ALK, deserve further investigation. Comprehensive analysis of molecular signatures of TW2.6 and animal studies will guide the future precision medicine.

Clinical trial indentification

N/A

Legal entity responsible for the study

N/A

Funding

National Taiwan University Hospital

Disclosure

All authors have declared no conflicts of interest.