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<p>PARP inhibitors (PARPi) selectively target cancers with homologous recombination deficiency (HRD), yet emerging evidence suggests that additional determinants beyond BRCA/HRD status modulate PARPi response. Here, by integrating unbiased proteomic profiling with systematic drug-response phenotyping across 11 ovarian cancer cell lines, we identify MAP2K6 as a previously unrecognized regulator of PARP1 activation and an important determinant of PARP inhibitor sensitivity in BRCA-wild-type ovarian cancer. MAP2K6 promotes global PARP1-mediated PARylation and enhances cellular responsiveness to the PARP inhibitor olaparib both in vitro and in vivo. Mechanistically, MAP2K6 can phosphorylate and activate HMGA1, which in turn transcriptionally upregulates NAMPT, resulting in increased intracellular NAD<sup>+</sup> levels, and sustained PARP1 activation. Genetic depletion of HMGA1 or NAMPT abolishes MAP2K6-driven PARylation and PARPi sensitization, whereas loss of MAP2K6 reduces NAD<sup>+</sup> levels, attenuates PARP1 activation, and confers resistance to PARPi. We propose that MAP2K6 promotes PARP inhibitor sensitivity by coupling metabolic control of NAD<sup>+</sup> supply to PARP1 activation, thereby potentially helping extend the therapeutic scope of PARP inhibition beyond homologous recombination-deficient ovarian cancer.</p>

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MAP2K6 reprograms NAD+ metabolism via the HMGA1–NAMPT axis to sensitize ovarian cancer cells to PARP inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月17日

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  • Ming Wen,
  • Zhuohang Chen,
  • Dongdong Zhan,
  • Mingwei Liu,
  • Shuran Tan,
  • Fang Zhu,
  • Siyu Yang,
  • Jinru Xie,
  • Yu Zhang,
  • Jianjian Li,
  • Lunquan Sun,
  • Rong Tan

摘要

PARP inhibitors (PARPi) selectively target cancers with homologous recombination deficiency (HRD), yet emerging evidence suggests that additional determinants beyond BRCA/HRD status modulate PARPi response. Here, by integrating unbiased proteomic profiling with systematic drug-response phenotyping across 11 ovarian cancer cell lines, we identify MAP2K6 as a previously unrecognized regulator of PARP1 activation and an important determinant of PARP inhibitor sensitivity in BRCA-wild-type ovarian cancer. MAP2K6 promotes global PARP1-mediated PARylation and enhances cellular responsiveness to the PARP inhibitor olaparib both in vitro and in vivo. Mechanistically, MAP2K6 can phosphorylate and activate HMGA1, which in turn transcriptionally upregulates NAMPT, resulting in increased intracellular NAD+ levels, and sustained PARP1 activation. Genetic depletion of HMGA1 or NAMPT abolishes MAP2K6-driven PARylation and PARPi sensitization, whereas loss of MAP2K6 reduces NAD+ levels, attenuates PARP1 activation, and confers resistance to PARPi. We propose that MAP2K6 promotes PARP inhibitor sensitivity by coupling metabolic control of NAD+ supply to PARP1 activation, thereby potentially helping extend the therapeutic scope of PARP inhibition beyond homologous recombination-deficient ovarian cancer.