Targeting MARK2-HDAC signaling to overcome paclitaxel resistance in pancreatic cancer

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Abstract Text Many antitubulin agents, such as paclitaxel (Taxol), have been used extensively for treatment of several types of cancer, including breast, ovarian, lung, and pancreatic cancers. Despite their wide use in cancer treatment, however, patient response is highly variable and drug resistance remains a major clinical issue. It is therefore essential to identify prognostic markers to predict the patient response and to enhance drug sensitivity. Through biochemical and cell-based kinome-wide screens, we identified MARK2 (microtubule affinity- regulating kinase 2) as a critical regulator for Taxol chemosensitivity in PDAC (pancreatic ductal adenocarcinoma) cells. We show that MARK2 is phosphorylated in response to antitubulin chemotherapeutics. We further identified the corresponding kinase and mapped phosphorylation sites. MARK2 determines Taxol cytotoxicity in PDAC cells without affecting growth under normal conditions. Mechanistically, our findings also suggest that MARK2 controls Taxol chemosensitivity by regulating class IIa HDACs (histone deacetylase). MARK2 directly phosphorylates HDAC4 upon Taxol treatment. MARK2-phosphorylated HDAC4 positively regulates YAP (yes-associated protein) activity and controls expression of YAP target genes specifically induced by Taxol. Inhibition of HDACs sensitizes PDAC cells to Taxol treatment in vitro and in immunocompetent animals. Our hypothesis is that the MARK2-HDACs axis functions as a therapeutic target for overcoming Taxol resistance in PDAC patients. We will test our central hypothesis by three specific aims. Aim 1: Determine the role and regulation of MARK2 in response to antitubulin chemotherapeutics; Aim 2: Elucidate the downstream effectors and mechanisms of MARK2 in response to Taxol chemotherapeutics; Aim 3: Targeting HDACs and serine metabolism to overcome Taxol resistance in PDAC. The identification of new regulators and/or signaling pathways triggered by antitubulin drugs will shed light on the mechanisms underlying chemoresistance. Our study suggests that combining HDAC inhibitors with antitubulin agents (e.g. Taxol) will have enhanced efficacy in treatment of drug-resistant and/or recurrent PDAC patients.