Abstract 5163: Determining the role of septin expression in response of breast cancer patients to microtubule targeted chemotherapy

Abstract

Abstract Drugs that disrupt the microtubule cytoskeleton, including both microtubule stabilizing taxanes and destabilizers like eribulin, are regularly used in the treatment of metastatic breast cancer. However, there are currently no molecular biomarkers to guide their use. Septins, a class of small GTPases, interact with both microtubules and actin to functionally link these cytoskeletal components and regulate cell biological processes shown to be critical for the invasion and migration of cancer cells. In particular, septin 9 (SEPT9) directly interacts directly with microtubules through an N-terminal domain on the longest isoform, SEPT9i1, which is sufficient to promote migration and invasion of breast cancer cells in vitro. We hypothesized that the relative expression of septin9 isoforms in breast tumors could play a role in their response to treatment with microtubule-targeted chemotherapy, particularly in the metastatic setting. A retrospective investigation of the relationship between septin expression and response to taxane chemotherapy was conducted utilizing full transcriptome sequencing data from biopsies of 75 breast cancer patients treated at our NCI-Designated Mays Cancer Center who received molecular profiling through Caris Life Sciences. Levels of total SEPT9 expression as well as the expression of specific variants that encode mechanistically distinct septin9 isoforms, SEPT9v1, v2, and v3, were determined for each sample and correlated with demographic, treatment, and outcome data for these patients. The oncogenic sept9_v1 variant (which produces the septin9_i1 isoform) was detected in over half of tumors and those with the highest total septin9 expression also expressed significantly higher levels of this isoform. Strikingly, the expression of total septin9, as well as the v3 variant, was significantly increased in taxane-treated patients who survived over a year after diagnosis with metastatic breast cancer, suggesting that septin9 expression could be a molecular correlate of response to taxane chemotherapy. We found that the expression of total septin9 and its variants was not significantly correlated with race, ethnicity, or cancer type suggesting that our findings would apply to our patient population as a whole, which is over 50% Hispanic. These data were used to support an ongoing prospective study to determine effect of septin expression on response to taxane chemotherapy in the neoadjuvant setting and determine the effect of taxane treatment on septin expression by comparing samples pre and post treatment. Together this work supports our overall goal of identifying predictive biomarkers to facilitate the use of microtubule targeted chemotherapy in a more personalized manner. Citation Format: Tamarah Aldawoodi, Jacob Nathaniel Essif, Amna Naqvi, Lauren D. Boyle, Daniela Urueta Portillo, Kate Lathrop, April L. Risinger. Determining the role of septin expression in response of breast cancer patients to microtubule targeted chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5163.