MAP4 phosphorylation induced by ARID1A loss sensitizes colorectal cancer cells to EMP

Mutational inactivation of the tumor suppressor gene ARID1A is a key driver of tumorigenesis in various types of cancer, making it a promising therapeutic target for anticancer drug development. Here, we performed a synthetic lethal drug screening in an approved drug library with ARID1A isogenic CRC cell lines and identified estramustine phosphate sodium (EMP), an FDA approved antimicrotubule chemotherapy drug, as a synthetic lethal partner of ARID1A. ARID1A loss increases the vulnerability to EMP. Mechanistically, ARID1A loss increases the phosphorylation level of MAP4 (microtubule-associated protein 4), which is a key microtubule dynamics regulator in cancer cells. Therefore, ARID1A loss attenuates microtubule stabilizing activity of MAP4 and creates a dependence on its residual activity. By targeting MAP4, EMP severely disrupts microtubule dynamics, affecting bipolar spindle formation and positioning, and inducing mitotic cell death in ARID1A-deficient cells. Furthermore, we identified that MAP4 is phosphorylated by PI3K, which is activated by ARID1A loss. These findings highlight MAP4 as a key regulator of microtubule dynamics in ARID1A-deficient cells and unveil a novel synthetic lethality relationship between ARID1A and EMP.