Abstract 3691A: Targeting MARK2-HDAC-YAP signaling to overcome paclitaxel resistance in PDAC

Abstract

Abstract Nanoparticle albumin-bound (Nab)-paclitaxel (taxol) combined with gemcitabine has been approved as a first-line chemotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) patients. However, the response rate is still very low due to the occurrence of drug resistance and attempts in reversing the resistance have not been successful in the clinic. MARK (microtubule affinity-regulating kinase) proteins (MARK1-4) are critical for microtubule dynamics by modulating MAPs (microtubule-associated proteins). They are members of the AMPK/Snf1 family and control cell polarity and asymmetric cell division. Dysregulation of MARKs has also been associated with pathological conditions such as cancer and Alzheimer disease. Several recent studies showed that MARK family members are important regulators of Hippo-YAP (Yes-associated protein) signaling, which is critical in cancer development, drug resistance, and stem cell biology. Through Phos-tag-based kinome-wide screens, we identified MARK2 as a critical determinant for mitotic progression and paclitaxel chemosensitivity. MARK2 is phosphorylated by cyclin-dependent kinase 1 (CDK1) during paclitaxel-induced mitotic arrest and normal mitosis. MARK2 inhibition did not affect growth under normal conditions, but greatly sensitized PDAC cells to paclitaxel-induced apoptosis. Mechanistically, our findings also suggest that MARK2 controls paclitaxel chemosensitivity by regulating class IIa HDACs (histone deacetylase). MARK2 directly phosphorylates HDAC4 on multiple sites upon paclitaxel treatment. Inhibition (with knockdown or inhibitors) of HDACs significantly enhanced paclitaxel-induced cell death in a MARK2-phosphorylation dependent manner in PDAC cells. MARK2-phosphorylated HDAC4 positively regulates YAP (the transcriptional coactivator of the Hippo pathway) activity and controls expression of YAP target genes induced by paclitaxel. MARK2, class IIa HDACs, and YAP expression levels are upregulated and positively correlated in PDAC patients. Importantly, combination of HDAC inhibition (Vorinostat/SAHA, FDA-approved) and paclitaxel overcomes paclitaxel-resistance in preclinical PDAC animal models. Together, our findings reveal the MARK2-HDAC-YAP axis as a druggable target for overcoming paclitaxel resistance in PDAC. Citation Format: Yongji Zeng, Yuanhong Chen, Jixin Dong. Targeting MARK2-HDAC-YAP signaling to overcome paclitaxel resistance in PDAC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3691A.