YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage

Abstract

Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knock-down sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC.

YAP promotes erlotinib resistance in human non-small cell lung cancer cells

“…We found that inhibition of YAP by siRNA increase erlotinib's cytotoxicity to H1975 cells. Verteporfin is a small molecule that inhibits TEAD-YAP interaction, and several studies have used it as YAP inhibitor to suppress YAP-induced tumorigenesis [10, 14, 27–29]. In our study, we verified that verteporfin decreased YAP protein expression, GTIIC reporter activity and mRNA expression of downstream genes AREG and CTGF in H1975 cells.…”

YAP Inhibition by Resveratrol via Activation of AMPK Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine

“…However, YAP’s function in chemotherapeutic drug response is largely unknown in pancreatic cancer cells. Ciamporcero et al [47] demonstrated that YAP overexpression protected, whereas YAP knockdown sensitized, urothelial cell carcinoma (UCC) cells to chemotherapy and radiation effects by increasing the accumulation of DNA damage and apoptosis. Verteporfin, a pharmacological YAP inhibitor, could inhibit tumor cell proliferation and restore sensitivity to cisplatin.…”

Verteporfin, a suppressor of YAP–TEAD complex, presents promising antitumor properties on ovarian cancer

“…In accordance with our in vitro findings, the results showed that VP could cause a remarkable effect on production of ascites and a moderate effect on tumor growth of OC in vivo. Recent studies found that better anticancer treatment effect could be achieved in VP when in combination with chemoagents 16,32. Additionally, knockdown of YAP could sensitize OC cells to various cancer therapeutic agents in vitro 33.…”