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<p>CDK4/6 inhibitors in combination with endocrine therapy are now used as front-line treatment for patients with estrogen-receptor positive (ER+) breast cancer. While this combination improves overall survival, the mechanisms of disease progression remain poorly understood. Here, we performed unbiased genome-wide CRISPR/Cas9 knockout screens using endocrine sensitive ER+ breast cancer cells to identify novel drivers of resistance to combination endocrine therapy (tamoxifen) and CDK4/6 inhibitor (palbociclib) treatment. Our screens identified the inactivation of JNK signalling, including loss of the kinase <i>MAP2K7</i>, as a key driver of drug insensitivity. We developed multiple CRISPR/Cas9 knockout ER+ breast cancer cell lines (MCF-7 and T-47D) to investigate the effects of <i>MAP2K7</i> and downstream <i>MAPK8</i> and <i>MAPK9</i> loss. <i>MAP2K7</i> knockout increased metastatic burden in vivo and led to impaired JNK-mediated stress responses, as well as promoting cell survival and reducing senescence entry following endocrine therapy and CDK4/6 inhibitor treatment. Mechanistically, this occurred via loss of the AP-1 transcription factor c-JUN, leading to an attenuated response to combination endocrine therapy plus CDK4/6 inhibition. Furthermore, analysis of clinical datasets found that inactivation of the JNK pathway was associated with increased metastatic burden, and low pJNK<sup>T183/Y185</sup> activity correlated with a poorer response to systemic endocrine and CDK4/6 inhibitor therapies in both early-stage and metastatic ER+ breast cancer cohorts. Overall, we demonstrate that suppression of JNK signalling enables persistent growth during combined endocrine therapy and CDK4/6 inhibition. Our data provides the pre-clinical rationale to stratify patients based on JNK pathway activity prior to receiving combination endocrine therapy and CDK4/6 inhibition.</p>

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JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月19日

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  • Sarah Alexandrou,
  • Christine S. Lee,
  • Kristine J. Fernandez,
  • Celine E. Wiharja,
  • Leila Eshraghi,
  • John Reeves,
  • Daniel A. Reed,
  • Neil Portman,
  • Zoe Phan,
  • Heloisa H. Milioli,
  • Iva Nikolic,
  • Antonia L. Cadell,
  • David R. Croucher,
  • Kaylene J. Simpson,
  • Elgene Lim,
  • Theresa E. Hickey,
  • Ewan K. A. Millar,
  • Carla L. Alves,
  • Henrik J. Ditzel,
  • C. Elizabeth Caldon

摘要

CDK4/6 inhibitors in combination with endocrine therapy are now used as front-line treatment for patients with estrogen-receptor positive (ER+) breast cancer. While this combination improves overall survival, the mechanisms of disease progression remain poorly understood. Here, we performed unbiased genome-wide CRISPR/Cas9 knockout screens using endocrine sensitive ER+ breast cancer cells to identify novel drivers of resistance to combination endocrine therapy (tamoxifen) and CDK4/6 inhibitor (palbociclib) treatment. Our screens identified the inactivation of JNK signalling, including loss of the kinase MAP2K7, as a key driver of drug insensitivity. We developed multiple CRISPR/Cas9 knockout ER+ breast cancer cell lines (MCF-7 and T-47D) to investigate the effects of MAP2K7 and downstream MAPK8 and MAPK9 loss. MAP2K7 knockout increased metastatic burden in vivo and led to impaired JNK-mediated stress responses, as well as promoting cell survival and reducing senescence entry following endocrine therapy and CDK4/6 inhibitor treatment. Mechanistically, this occurred via loss of the AP-1 transcription factor c-JUN, leading to an attenuated response to combination endocrine therapy plus CDK4/6 inhibition. Furthermore, analysis of clinical datasets found that inactivation of the JNK pathway was associated with increased metastatic burden, and low pJNKT183/Y185 activity correlated with a poorer response to systemic endocrine and CDK4/6 inhibitor therapies in both early-stage and metastatic ER+ breast cancer cohorts. Overall, we demonstrate that suppression of JNK signalling enables persistent growth during combined endocrine therapy and CDK4/6 inhibition. Our data provides the pre-clinical rationale to stratify patients based on JNK pathway activity prior to receiving combination endocrine therapy and CDK4/6 inhibition.