Targeting the gain-of-function of mutant p53 (mutp53) is a critical yet elusive goal in triple-negative breast cancer (TNBC), however, while the roles of microtubule affinity-regulating kinases (MARKs) in cancer progression are often debated, their relationship with the oncogenic mutp53 pathway has remained a blind spot.

Here, we identify MARK2 as the sole MARK family member uniquely upregulated in TNBC and linked to poor survival, and we demonstrate that it sustains oncogenic signaling by stabilizing mutp53 in the nucleus. Unlike its family members, MARK2 interacts directly with mutp53 via its UBA and Spacer domains, acting as a molecular “shield” that prevents ubiquitin-mediated degradation; notably, this protective effect occurs independently of MARK2’s kinase activity, explaining why kinase inhibitors fail to curb TNBC growth.

This work provides a new strategy based on disrupting the MARK2-mutp53 interaction through dominant-negative mutants (MARK2-ΔUBA/ΔSpacer) to restore mutp53 degradation and inhibit tumor growth, and reveals the critical role of MARK2 as the “guardian of the villain” in TNBC. The work entitled “Targeting of MARK2, but not other MARKs, suppresses TNBC progression by inhibition of the mutant p53-driven signaling pathway” was published on Chinese Journal of Natural Medicines. (published on April 20, 2026).
DOI:10.1016/S1875-5364(26)61172-7