Microtubule affinity-regulating kinase 2 is associated with DNA damage response and cisplatin resistance in non-small cell lung cancer

Abstract

Microtubule affinity-regulating kinases (MARKs) are involved in several cellular functions but few studies have correlated MARK kinase expression with cancer, and none have explored their role in lung cancer. In this study, we identified MARK2 as frequently disrupted by DNA hypomethylation and copy gain, resulting in concordant overexpression in independent lung tumor cohorts and we demonstrate a role for MARK2 in lung tumor biology. Manipulation of MARK2 in lung cell lines revealed its involvement in cell viability and anchorage-independent growth. Analyses of both manipulated cell lines and clinical tumor specimens identified a potential role for MARK2 in cell cycle activation and DNA repair. Associations between MARK2 and the E2F, Myc/Max and NF-κB pathways were identified by luciferase assays and in-depth assessment of the NF-κB pathway suggests a negative association between MARK2 expression and NF-κB due to activation of non-canonical NF-κB signaling. Finally, we show that high MARK2 expression levels correlate with resistance to cisplatin, a standard first line chemotherapy for lung cancer. Collectively, our work supports a role for MARK2 in promoting malignant phenotypes of lung cancer and potentially modulating response to the DNA damaging chemotherapeutic, cisplatin. What's new? Microtubule affinity-regulating kinases (MARKs) have been implicated in multiple cellular processes, including intracellular transport, cell polarity, and cell migration. Yet, few studies have correlated MARK kinase expression with cancer, and none have explored their role in lung cancer. Here, the authors describe for the first time highly frequent DNA and RNA-level disruption of MARK2 in clinical non-small cell lung cancer (NSCLC) cases. They provide evidence supporting a novel role for MARK2 in promoting malignant phenotypes of lung cancer, and in potentially modulating response to the DNA damaging chemotherapeutic agent cisplatin.