p85β alters response to EGFR inhibitor in ovarian cancer through p38 MAPK-mediated regulation of DNA repair

Abstract

EGFR signaling promotes ovarian cancer tumorigenesis, and high EGFR expression correlates with poor prognosis. However, EGFR inhibitors alone have demonstrated limited clinical benefit for ovarian cancer patients, owing partly to tumor resistance and the lack of predictive biomarkers. Cotargeting EGFR and the PI3K pathway has been previously shown to yield synergistic antitumor effects in ovarian cancer. Therefore, we reasoned that PI3K may affect cellular response to EGFR inhibition. In this study, we revealed PI3K isoform-specific effects on the sensitivity of ovarian cancer cells to the EGFR inhibitor erlotinib. Gene silencing of PIK3CA (p110α) and PIK3CB (p110β) rendered cells more susceptible to erlotinib. In contrast, low expression of PIK3R2 (p85β) was associated with erlotinib resistance. Depletion of PIK3R2 , but not PIK3CA or PIK3CB , led to increased DNA damage and reduced level of the nonhomologous end joining DNA repair protein BRD4. Intriguingly, these defects in DNA repair were reversed upon erlotinib treatment, which caused activation and nuclear import of p38 MAPK to promote DNA repair with increased protein levels of 53BP1 and BRD4 and foci formation of 53BP1. Remarkably, inhibition of p38 MAPK or BRD4 re-sensitized PIK3R2 -depleted cells to erlotinib. Collectively, these data suggest that p38 MAPK activation and the subsequent DNA repair serve as a resistance mechanism to EGFR inhibitor. Combined inhibition of EGFR and p38 MAPK or DNA repair may maximize the therapeutic potential of EGFR inhibitor in ovarian cancer.

Adverse Toxic Effects of Tyrosine Kinase Inhibitors on Non-Target Zebrafish Liver (ZFL) Cells

“…For ERL, Kryeziu et al [ 65 ] showed that 20 µM ERL did not induce DNA damage (alkaline comet assay) in A549 cells after 6 h exposure [ 65 ]. Contrary to this and our study, Mak et al [ 66 ] showed that ERL (10 µM) increases the percentage of tail DNA in human ovarian cancer cells (SKOV-3 cells), but only after a longer exposure time (72 h).…”

Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer

“…To this end, we first performed GOEA considering all 549 driver genes (Supplementary Table 08) and then reconstructed the specific activation time of each significant GO term by calculating the proportion of genes it included from each cluster. GOEA analysis of the 549 driver genes (Figure 4B) revealed several biological processes previously linked to drug resistance in other cancer types, including lysosome biogenesis, Reactive Oxygen Species (ROS) homeostasis, and fatty acid metabolism (48)(49)(50)(51)(52)(53)(54), as well as specific genes linked to EGFR resistance, such as PDGF-C (55), FGF2 (56,57), PIK3R2 (58), HRAS (59), MAPK3 (60,61), GAS6 (62), and BAX (63) (Figure 4C). Interestingly, PDGF-C and FGF2 are PDGFR-α and FGFR ligands, respectively.…”

Role of p38 MAP kinase in cancer stem cells and metastasis

“…Additionally, p38ɑ directly phosphorylates and activates CtIP, which is responsible for DNA double-strand break resection and proper DNA repair [ 96 ]. Moreover, activated p38 MAPK signaling increases the expression levels of BRD4 and 53BP1 (key DNA damage response factors that promote nonhomologous end joining repair), thereby repairing damaged DNA and protecting cells from apoptosis [ 97 ]. p38 inhibition could be utilized to prevent the activation of cell-cycle checkpoints, particularly the G2 checkpoint, and DNA repair pathways in order to increase the accumulation of DNA damage in CSCs, resulting in induction of apoptosis.…”