APC truncating mutations in Middle Eastern Population: Tankyrase inhibitor is an effective strategy to sensitize APC mutant CRC To 5-FU chemotherapy

• Published in: Biomedicine & pharmacotherapy 2020-01, Vol.121, p.109572, Article 109572
• Main Authors: Siraj, Abdul K., Kumar Parvathareddy, Sandeep, Pratheeshkumar, Poyil, Padmaja Divya, Sasidharan, Ahmed, Saeeda Omer, Melosantos, Roxanne, Begum, Rafia, Concepcion, Rica Micaela J.A., Al-Sanea, Nasser, Ashari, Luai H, Abduljabbar, Alaa, Al-Dayel, Fouad, Al-Kuraya, Khawla S.
• Format: Article
• Language: English
• Subjects: APC; Colorectal cancer; Short truncating mutation; Tankyrase inhibitors
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.109572

[Display omitted] •In Saudi Arabia, CRC is the second most common cancer.•In our cohort, APC mutation was independent predictor of superior overall survival.•The type of APC mutation (short/long truncating) had no impact on clinical outcome.•TNKSi selectively target APC mutated CRC cells and overcome chemoresistance.•TNKSi with 5-FU would be a useful therapeutic approach for a subset of CRCs. Colorectal Cancer (CRC) is highly heterogeneous for which prognosis is dependent mainly on clinical staging. There is a need to stratify subpopulations of CRC on molecular basis to better predict outcome and therapy response. Truncating mutations in adenomatous polyposis coli (APC) are well-described events in CRC carcinogenesis. Clinical and genotypic characterization of Middle Eastern CRC based on presence and type of APC was determined in 412 CRC tumors using modern next generation sequencing. APC truncating mutations were identified in 58.2% (240/412) of CRCs. Overall, mutation was significant predictor of superior overall survival. Further, the type of APC mutations (short or long) did not have impact on clinical outcome. However, in vitro analysis showed difference between CRC cell lines carrying short truncating APC vs CRC cells that carry long truncating APC mutation in response to 5-flourouracil (5-FU). Importantly, we were able to overcome the resistance to 5-FU seen in CRC cells carrying short APC by tankyrase inhibitor, XAV939, thereby inhibiting Wnt/β-catenin signaling cascade. Overall, our results showed that APC mutation status plays an important role in predicting overall survival in Middle Eastern population. Furthermore, in vitro data showed that selective targeting of APC mutated CRC by tankyrase inhibitor can be an effective strategy to overcome 5-FU resistance in CRC cells.