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.

EGFR信号传导促进卵巢癌肿瘤发生，EGFR高表达与预后不良相关。然而，仅 EGFR 抑制剂对卵巢癌患者的临床益处有限，部分原因是肿瘤耐药性和缺乏预测性生物标志物。先前已显示共靶向 EGFR 和 PI3K 途径在卵巢癌中产生协同抗肿瘤作用。因此，我们推断 PI3K 可能会影响细胞对 EGFR 抑制的反应。在这项研究中，我们揭示了 PI3K 亚型对卵巢癌细胞对 EGFR 抑制剂厄洛替尼敏感性的特异性影响。PIK3CA (p110α) 和PIK3CB (p110β)的基因沉默使细胞对厄洛替尼更敏感。相反，PIK3R2的低表达(p85β) 与厄洛替尼耐药有关。PIK3R2的消耗，而不是PIK3CA或PIK3CB的消耗，导致 DNA 损伤增加和非同源末端连接 DNA 修复蛋白 BRD4 的水平降低。有趣的是，这些 DNA 修复缺陷在厄洛替尼治疗后被逆转，这导致 p38 MAPK 的激活和核输入以促进 DNA 修复，增加 53BP1 和 BRD4 的蛋白质水平以及 53BP1 的病灶形成。值得注意的是，p38 MAPK 或 BRD4 的抑制使PIK3R2重新敏感- 厄洛替尼耗尽细胞。总的来说，这些数据表明 p38 MAPK 激活和随后的 DNA 修复可作为 EGFR 抑制剂的抗性机制。EGFR 和 p38 MAPK 或 DNA 修复的联合抑制可以最大限度地提高 EGFR 抑制剂在卵巢癌中的治疗潜力。