Oral squamous cell carcinoma (OSCC) is one of the most common forms of head and neck cancer, with more than half of the global mortality occurring in Asia. The current treatment regimens for OSCC are of limited benefit to the patients and the development of new targeted therapies is very much needed. In our previous study using genome-wide CRISPR/Cas9 screen to identify the genetic vulnerabilities for OSCC, we have successfully identified two key fitness genes - YAP1 and WWTR1 (TAZ) of the Hippo signaling pathway as potential therapeutic targets for OSCC. We discovered that CRISPR/Cas9-mediated knockout of either YAP1 or WWTR1 in the YAP1- or WWTR1-dependent OSCC cell lines resulted in the down-regulation of pro-proliferative genes such as the CTGF and CYR61. Further, both YAP1 and WWTR1 have separately been implicated as potential mediators of resistance to cisplatin, a common chemotherapy used for the treatment of OSCC patients. Inhibition of the interaction between either YAP1 or WWTR1 with their downstream binding partners, such as the transcription factor, TEAD, has been one of the main focus for therapeutic intervention. However, this has not been examined in the context of OSCC. We, therefore, aim to i) identify and evaluate the anti-proliferative effect of existing YAP1/WWTR1 inhibitors on YAP1/WWTR1-dependent OSCC, ii) evaluate the synergistic effect of combining the YAP1/WWTR1 inhibitors with cisplatin in controlling OSCC growth. We identify two putative inhibitors of YAP/WWTR1/TEAD - Verteporfin and CA3. We show that compared to Verteporfin, the new inhibitor, CA3 exerts a more prominent anti-proliferative effect on the OSCC models that are dependent on either YAP1 or WWTR1, with IC50 in the nanomolar range. We then test the effect of combining CA3 (at 0.5µM and 1µM) with various dosages of cisplatin and demonstrated strong synergistic effects in OSCC across most combinations. We show that CA3 sensitizes OSCC cells to cisplatin at concentrations as low as 0.5µM. Our results further confirm that YAP1/TAZ are important therapeutic targets in OSCC and the treatment of YAP1/TAZ inhibitors could sensitize the OSCC cells to cisplatin. Further investigation is warranted to uncover the mechanism underlying YAP/TAZ-mediated cisplatin sensitivity in OSCC to improve the proportion of OSCC patients who could respond to cisplatin.

Citation Format: Annie Wai Yeeng Chai, Pei San Yee, Shi Mun Yee, Sok Ching Cheong. Targeting OSCC fitness genes YAP1 and WWTR1 via synergistic killing of CA3 in combination with cisplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1226.