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PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer
Santiago-Gómez, Angélica Kedward, T Simoes, Bruno M Dragoni, I NicAmhlaoibh, R Trivier, E Sabin, V Gee, J Sims, A Howell, Sacha J
Santiago-Gómez, Angélica
Kedward, T
Simoes, Bruno M
Dragoni, I
NicAmhlaoibh, R
Trivier, E
Sabin, V
Gee, J
Sims, A
Howell, Sacha J
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Abstract
Despite the effectiveness of endocrine therapies to treat estrogen receptor-positive (ER+) breast tumours, two thirds of patients will eventually relapse due to de novo or acquired resistance to these agents. Cancer Stem-like Cells (CSCs), a rare cell population within the tumour, accumulate after anti-estrogen treatments and are likely to contribute to their failure. Here we studied the role of p21-activated kinase 4 (PAK4) as a promising target to overcome endocrine resistance and disease progression in ER + breast cancers. PAK4 predicts for resistance to tamoxifen and poor prognosis in 2 independent cohorts of ER + tumours. We observed that PAK4 strongly correlates with CSC activity in metastatic patient-derived samples irrespective of breast cancer subtype. However, PAK4-driven mammosphere-forming CSC activity increases alongside progression only in ER + metastatic samples. PAK4 activity increases in ER + models of acquired resistance to endocrine therapies. Targeting PAK4 with either CRT PAKi, a small molecule inhibitor of PAK4, or with specific siRNAs abrogates CSC activity/self-renewal in clinical samples and endocrine-resistant cells. Together, our findings establish that PAK4 regulates stemness during disease progression and that its inhibition reverses endocrine resistance in ER + breast cancers.
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Date
2019
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Santiago-Gomez A, Kedward T, Simoes BM, Dragoni I, NicAmhlaoibh R, Trivier E, et al. PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer. Cancer Lett. 2019;458:66-75.