The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast cancer. Everolimus is an mTORC1 inhibitor used in metastatic estrogen receptor-positive (ER+) and epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, mTORC1 inhibitors have limited efficacy in other breast cancer subtypes. We sought to discover collateral sensitivities to mTORC1 inhibition that could be exploited to improve therapeutic response. Using a mouse model of breast cancer that is intrinsically resistant to mTORC1 inhibition, we found that rapamycin alters the expression of numerous extracellular matrix genes, suggesting a potential role for integrins/FAK in controlling mTORC1-inhibitor efficacy. FAK activation was also inversely correlated with rapamycin response in breast cancer cell lines. Supporting its potential utility in patients, FAK activation was observed in >50% of human breast cancers. While blocking FAK in mouse models of breast cancer that are highly responsive to rapamycin had no impact on tumor growth, FAK inhibition sensitized rapamycin-resistant tumors to mTORC1 inhibition. These data reveal an innate dependency on FAK when mTORC1 signaling is lost in tumors that are resistant to mTORC1 inhibitors. They also suggest a precision medicine approach to improving mTORC1 inhibitor efficacy in resistant cancers by suppressing FAK signaling.
Mitotic kinases are essential for cell cycle progression, and several mitotic kinase inhibitors have been developed to target the uncontrolled proliferation of cancer cells. However, despite their efficacy in preclinical models, mitotic kinase inhibitors are generally considered poor therapeutic targets due to their off target effects in other rapidly proliferating tissues and subsequent toxicity. However, preliminary data in our lab shows that relative to non-transformed cells, triple negative breast cancer (TNBC) cells are selectively sensitive to inhibition of the mitotic kinase NEK2 compared to other mitotic kinase inhibitors. Therefore, we hypothesize that NEK2 is a targetable vulnerability of TNBC. To begin to understand the role of NEK2 in TNBC, we performed RNA-sequencing following NEK2 silencing and found increased expression of genes important at the G1/S cell cycle transition. This transition is largely controlled by the RB-E2F signaling axis, where CDK4 and CDK6 are key players. CDK4/6 inhibitors have been FDA approved for the treatment of a subset of breast cancers. We investigated the impact of silencing NEK2 and treating with CDK4/6 inhibitors and found that loss of NEK2 sensitizes TNBC cells to CDK4/6 inhibition. Mechanistically, this combination causes a significant increase in genomic instability phenotypes. We tested the combination of NEK2 inhibition and CDK4/6 inhibition in vivo, and found that the combination significantly decreases mouse tumor volume without inducing toxicity. Mechanistically, the combination altered mitotic spindle genes in vivo, indicating an increase in genomic instability. Together, these data suggest that that NEK2 is a viable therapeutic target that could be used in combination with FDA approved CDK4/6 inhibitors for the treatment of aggressive breast cancers such as TNBC.
Citation Format: Jessica R. Bobbitt, Leslie Cuellar-Vite, Benjamin Bryson, Kristen Weber-Bonk, Ruth Keri. Targeting the mitotic kinase NEK2 potentiates CDK4/6 inhibitor efficacy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1433.
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