Abstract 5859: PLK1 predicts aggressive behavior in CRC patients and its inhibition reverse chemoresistance in CRC cells

Abstract Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase, that is involved in multiple stages of cell cycle progression in mammals. Dysregulation of PLK1 has been found in a variety of human cancers and was associated with poor prognoses in various cancers. However, its role in the pathogenesis of CRC from Middle Eastern ethnicity has not yet been explored. Therefore, we examined the expression of PLK1 protein in a large cohort of over 1000 Middle Eastern CRC cases by immunohistochemistry. Correlation with clinico-pathological parameters were performed. PLK1 overexpression was noted in 60. 3% (693/1149) CRC cases and was significantly associated with larger tumor size (T3/T4 tumors), lymphnode metastasis, Stage III tumors, MSI-H status and p-ERK1/2 over-expression. Interestingly, on multivariate logistic regression analysis, we found that PLK1 was an independent predictor of lymphnode metastasis. However, no association was noted between PLK1 expression and clinical outcomes (DFS, RFS, OS, CSS). Our in vitro experimentation revealed that CRC cells expressing high levels of PLK1 exhibited resistance to 5-Fu treatment, whereas cells with low PLK1 expression demonstrated sensitivity to the treatment. To explore the role of PLK1 on chemoresistance, we inhibited PLK1 using specific inhibitor, volasertib and we showed that volasertib effectively reversed 5-Fu resistance in these cells. Furthermore, knockdown of PLK1 reduced the progression of epithelial-to-mesenchymal transition (EMT) and the stem cell-like properties in 5-Fu resistant cells, showing the role of PLK1 on inducing EMT and stemness in CRC. Interestingly, the forced expression of PLK1 triggered the activation of the CRAF-MEK-ERK-ZEB1 signaling cascade, whereas its inhibition led to the suppression of this cascade. In addition, we showed that silencing of ERK1/2 reversed the chemoresistance, EMT and stemness of PLK1 expressing CRC cell lines. Our findings underscore the significant role of PLK1 in conferring chemoresistance, and targeting PLK1 could represent a viable therapeutic approach for the treatment of patients with an aggressive subtype of CRC. Citation Format: Divya Padmaja, Maha Al-Rasheed, Pratheesh Kumar Poyil, Abdul K. Siraj, Sandeep Kumar Parvathareddy, Wael Haqawi, Fouad Al-Dayel, Khawla S. Al-Kuraya. PLK1 predicts aggressive behavior in CRC patients and its inhibition reverse chemoresistance in CRC cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5859.