The neural stem cell gene PAFAH1B1 controls cell cycle progression, DNA integrity, and paclitaxel sensitivity of triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is a highly aggressive disease with limited approved therapeutic options. The rapid growth and genomic instability of TNBC cells makes mitosis a compelling target. Indeed, a current mainstay of treatment is paclitaxel (Ptx), a taxane that stabilizes microtubules during mitosis. While initially effective, acquired resistance to Ptx is common, and other antimitotic therapies can be similarly rendered ineffective due to the development of resistance or systemic toxicity, underscoring the need for new therapeutic approaches. Interrogating CRISPR essentiality screens in TNBC cell lines, we identified LIS1 (PAFAH1B1) as a potential vulnerability in this disease. LIS1 regulates mitotic spindle orientation, proliferation, and cell migration during neurodevelopment, yet little is known regarding its function in breast cancer. We found that suppressing LIS1 expression in TNBC cells reduces cell number, while non-malignant cells remain unaffected. LIS1 suppression alters cell cycle dynamics, increasing mitotic duration and accumulation of cells in the G2/M phase. DNA damage is a common inducer of mitotic delays, and the suppression of LIS1 expression increases DNA double-strand breaks, indicating a requirement for sustained LIS1 expression to maintain the genomic integrity of TNBC cells. Lastly, LIS1 silencing substantially enhances these defects in cells that are taxane-resistant and sensitizes both parental and Ptx-resistant TNBC cells to Ptx. These results indicate that LIS1 may be a novel target for the development of new anti-mitotic agents for treating TNBC, particularly in the context of paclitaxel resistance.