MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation

Abstract

Platinum-based chemotherapeutics represent a mainstay of cancer therapy, but resistance limits their curative potential. Through a kinome RNAi screen, we identified microtubule-associated serine/threonine kinase 1 (MAST1) as a main driver of cisplatin resistance in human cancers. Mechanistically, cisplatin but no other DNA-damaging agents inhibit the MAPK pathway by dissociating cRaf from MEK1, while MAST1 replaces cRaf to reactivate the MAPK pathway in a cRaf-independent manner. We show clinical evidence that expression of MAST1, both initial and cisplatin-induced, contributes to platinum resistance and worse clinical outcome. Targeting MAST1 with lestaurtinib, a recently identified MAST1 inhibitor, restores cisplatin sensitivity, leading to the synergistic attenuation of cancer cell proliferation and tumor growth in human cancer cells and patient-derived xenograft models.

Hsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradation

“…Through mass spectrometry-based (MS-based) proteomic analysis, we identified hsp90B as a potential binding partner of MAST1 ( Figure 1B). Endogenous interaction between hsp90B and MAST1 was demonstrated by coimmunoprecipitation analysis in cisplatin-resistant sublines of human carcinoma KB-3-1 and lung cancer A549 cells ( Figure 1C) (7). We further explored whether the interaction is limited to the hsp90B isoform by comparing the interaction between MAST1 and hsp90B or hsp90A.…”

“…The mechanisms underlying cisplatin resistance are complex, and include reduction in the intracellular cisplatin level, enhanced damaged DNA repair, and activation of prosurvival signaling pathways often involving activation of the kinase MEK (2,6). We recently reported that a microtubule-associated serine/threonine kinase 1 (MAST1, also known as SAST170), which is known as a scaffold molecule that links the dystrophin and utrophin complex with microfilaments, is a common critical factor that drives cisplatin resistance in diverse types of human cancer, including head and neck, lung, and ovarian cancers (7,8). MAST1 confers cisplatin resistance through MEK1 reactivation by replacing its conventional kinase cRaf when cisplatin disrupts the interaction between MEK1 and cRaf (7).…”

“…We recently reported that a microtubule-associated serine/threonine kinase 1 (MAST1, also known as SAST170), which is known as a scaffold molecule that links the dystrophin and utrophin complex with microfilaments, is a common critical factor that drives cisplatin resistance in diverse types of human cancer, including head and neck, lung, and ovarian cancers (7,8). MAST1 confers cisplatin resistance through MEK1 reactivation by replacing its conventional kinase cRaf when cisplatin disrupts the interaction between MEK1 and cRaf (7). Abundance of MAST1 positively correlated with cisplatin resistance in primary tumors obtained from cancer patients who received cisplatin-containing chemotherapy.…”

“…Hsp90B confers cisplatin resistance to cancer cells mainly through MAST1 regulation. We previously reported that MAST1 plays a pivotal role in driving cisplatin resistance in human cancers (7). Hsp90 inhibitors are considered to be effective in overcoming cisplatin resistance, but their mechanism of action is unclear.…”

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

“…In addition, MEK1 reactivation is contributed to cancer cell resistance to cisplatin. This occurs by cisplatin inducible effects on dissociation of CRAF from MEK1 and further replacing CRAF with microtubule‐associated serine/threonine kinase 1 (MAST1) to reactivate MAPK pathway, so inhibition of MAST1 by agents like lestaurtinib could restore cisplatin sensitivity (Jaykumar et al, ; Jin et al, ).…”