MOB2 Loss Sensitizes Lung Cancer Cells to PARP Inhibition Through p53-Dependent DNA Damage Signaling

TL;DR

This study shows that losing the hMOB2 protein makes lung cancer cells more vulnerable to PARP inhibitors, especially when the p53 protein is active, suggesting a new way to improve cancer treatment.

Contribution

The study identifies hMOB2 as a novel modulator of PARP inhibitor sensitivity in lung cancer cells through p53-dependent DNA damage signaling.

Findings

hMOB2 depletion sensitizes lung cancer cells to PARP inhibitors like olaparib and rucaparib.

The sensitization effect depends on functional p53, as it was absent in p53-null cells but restored with p53 re-expression.

hMOB2 loss increases DNA damage and apoptosis without being cytotoxic on its own.

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors exploit defects in homologous recombination (HR) but show limited and heterogeneous efficacy in non-small-cell lung cancer (NSCLC), where canonical HR deficiency is uncommon. Identifying alternative molecular determinants that modulate PARP inhibitor sensitivity therefore remains an important objective. In this study, we examined the role of the NDR/Hippo-associated cofactor human MOB2 (hMOB2) in shaping PARP inhibitor responses in lung cancer cells. hMOB2 was depleted by siRNA in A549 and H1299 cell lines, and cell viability, long-term survival, DNA damage, and apoptosis were assessed using WST-1 assays, clonogenic assays, Western blotting, immunofluorescence, comet assays, and caspase-3 activity assays. p53 dependency was evaluated using p53-null H1299 cells and p53 reconstitution via retroviral transduction. hMOB2 depletion sensitized A549 cells to olaparib and rucaparib, resulting in a marked reduction in long-term clonogenic survival. This effect was associated with enhanced p53 phosphorylation, persistent γH2AX accumulation, increased DNA strand breaks, and caspase-3-dependent apoptosis, while hMOB2 loss alone was not intrinsically cytotoxic. Sensitization required functional p53, as it was absent in p53-null cells but restored upon p53 re-expression. These findings suggest that hMOB2 contributes to PARP inhibitor responses in lung cancer cells and underscore the complexity of PARP inhibitor sensitivity beyond classical HR deficiency.

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