A PP2A-mtATR-tBid axis links DNA damage-induced CIP2A degradation to apoptotic dormancy and therapeutic resistance in PDAC.

Abstract

DNA damage-based drugs are widely used in cancer therapy, yet resistance remains a significant challenge. In this study, we uncovered a non-DNA repair mechanism contributing to resistance in cancer cells. We found that in gemcitabine-resistant pancreatic ductal adenocarcinoma (PDAC) cells, CIP2A degradation via ubiquitination enhanced PP2A phosphatase activity, leading to the dephosphorylation of ATR at Ser428 in the cytoplasm. This dephosphorylation promoted the formation of the prolyl cis-isomeric form of ATR at its Ser428-Pro429 motif, a mitochondria-targeted antiapoptotic protein (mtATR). Surprisingly, the resistant PDAC cells paradoxically accumulated both mtATR and proapoptotic tBid at mitochondria, forming the mtATR-tBid complex. This complex silenced tBid, inducing apoptotic dormancy. Antagonizing mtATR, either through the PP2A inhibitor LB-100 or a cytoplasmic ATR-specific antibody, reactivated the pre-accumulated mitochondrial tBid and induced apoptosis in resistant PDAC cells. In an orthotopic PDAC mouse model, LB-100 alone significantly suppressed resistant tumor growth by disrupting the mtATR-tBid complex. These findings reveal a novel mechanism of resistance to DNA damage-based cancer drugs and introduce a new action mechanism of LB-100, which works through mtATR-tBid complex-mediated apoptotic dormancy triggered by CIP2A degradation-mediated PP2A activation. Disrupting the mtATR-tBid complex may represent a promising strategy to restore or sensitize resistant cancer cells to apoptosis.