Bobby Dow

Introduction: Breast cancer is the most common form of cancer in women worldwide, affecting 1 in 8 women over the course of their lifetime.¹ Upon diagnosis, the 5 year survival rates of breast cancer is 91 percent, with location and spread of the cancer greatly impacting the success of treatment and survival.¹ Current treatment option for breast cancer can range from the use of surgery to excise tumorous tissue, to the use of chemotherapy to kill cancerous cells with phrenological agents.² In Estrogen Receptor (ERα) positive breast cancer, over expression of ERα leads to upregulation of Cyclin D1 and the tumor cell cycle progression from G1 to S.³ Upon Cyclin D1 binding to CDK4/6, the complex phosphorylated Rb leading to E2F causing cell cycle progression and breast cancer progression.⁴ The use of CDK 4/6 inhibitors are a new and effective therapeutic agent in treating breast cancer, but over time resistance arises and treatment becomes ineffective. Upregulation of the FGFR1-PI3K-AKT pathways has been associated with CDK 4/6 inhibitor resistance. Methods: MCF-7 breast cancer cells susceptible to CDK 4/6 inhibitors were treated with prolonged ER inhibitor (fluvesterant) and the CDK 4/6 inhibitor (ribociclob), and an Open Reading Frame Kinome Screen was used to determine possible mechanisms of resistance.⁵ These possible changes in breast cancer cells were then confirmed in patient samples to indicate upregulation in genetic markers. By looking at both patient data and data from the kinome screen it was determined that upregulation of FGFR1 and PI3K result in CDK 4/6 inhibitor resistance. Cell culture of MFC-7 cells and SCID mice with MFC-7 breast cancer xenographs were then treated with either FGFR1 or PI3K inhibitors, and tumor viability was recorded.^5,6 Results: ER+ MCF-7 breast cancer cells, treated with prolonged CDK4/6 inhibitors showed resistance to treatment and upregulation of various genes associated with the FGFR1-PI3K-AKT pathway.^5.6 When these  MCF-7 cells were treated with either FGFR1 or PI3K inhibitors, tumor growth and survival greatly decreased. Using the same cell culture, it was also determined that triple combination therapy with Estrogen Receptor, CDK 4/6 and either FGFR1 or PI3K inhibitors had the greatest effect on tumor growth and overall viability of breast cancer cells.^5,6 Conclusion: Upregulation of proteins in the FGFR1-PI3K-AKT pathways leads to CDK4/6 inhibitor resistance and breast cancer survival. Inhibition of upregulated units in this pathway re-sensitizes cells to CDK4/6 treatment and results in tumor death.

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5. Formisano, L., Lu, Y., Servetto, A. et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat Commun 10, 1373 (2019). https://doi.org/10.1038/s41467-019-09068-2.
6. Herrera-Abreu MT, Palafox M, Asghar U, et al. Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer [published correction appears in Cancer Res. 2016 Oct 1;76(19):5907]. Cancer Res. 2016;76(8):2301-2313. doi:10.1158/0008-5472.CAN-15-0728.