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

Alexandrou, S; Lee, CS; Fernandez, KJ; Wiharja, CE; Eshraghi, L; Reeves, J; Reed, DA; Portman, N; Phan, Z; Milioli, HH; Nikolic, I; Cadell, AL; Croucher, DR; Simpson, KJ; Lim, E; Hickey, TE; Millar, EKA; Alves, CL; Ditzel, HJ; Caldon, CE

Author(s): Alexandrou, S; Lee, CS; Fernandez, KJ; Wiharja, CE; Eshraghi, L; Reeves, J; Reed, DA; Portman, N; Phan, Z; Milioli, HH; Nikolic, I; Cadell, AL; Croucher, DR; Simpson, KJ; Lim, E; Hickey, TE; Millar, EKA; Alves, CL; Ditzel, HJ; Caldon, CE;
Details: Publication Year 2025-08-19,Volume 44,Issue #1,Page 244
Journal Title: Journal of Experimental & Clinical Cancer Research
Publication Type: Research article
Abstract: 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 pJNK(T183/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.
Publisher: BioMed Central
Keywords: CDK4/6 inhibition; ER+ breast cancer; Endocrine therapy; JNK signalling; Palbociclib
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1186/s13046-025-03466-9
Open Access at Publisher's Site: https://doi.org/10.1186/s13046-025-03466-9
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-08-28 05:52:24

Last Modified: 2025-08-28 05:52:35