PAK1 activation as a common mechanism of endocrine therapy resistance in luminal A breast cancer models

Breast cancer is a highly heterogeneous disease, representing the most frequent malignancy and the second leading cause of cancer-related mortality in women worldwide. Among breast cancer subtypes, estrogen receptor-positive (ER+) tumors are often treated with endocrine therapies such as Tamoxifen or aromatase inhibitors (AIs), aimed at disrupting estrogen signaling. While these therapies are initially effective, up to 40% of patients eventually develop resistance, leading to disease relapse. The kinase p21-activated kinase 1 (PAK1), a key regulator of multiple oncogenic signaling pathways, has been previously implicated in resistance to Tamoxifen. However, its role in driving resistance to aromatase inhibitors remains unclear. In this study, we demonstrate that PAK1 contributes to resistance in both Tamoxifen and AI therapy contexts. Using global phospho-proteomic profiling, we observed elevated PAK1 activity in cell line models resistant to both therapies, with further increases following EGF stimulation. Notably, PAK1 inhibition effectively reduced cell proliferation in both resistance models, albeit with distinct effects on downstream PAK1 substrates. Our findings position PAK1 as a common mediator of resistance to endocrine therapies and offer valuable insights into the specific signaling networks involved in this process. These results suggest that targeting PAK1 may present a novel therapeutic strategy to overcome resistance in ER+ breast cancer, enhancing the efficacy of both Tamoxifen and AI treatments.