Priya Ramamoorthy

Introduction:  Triple Negative Breast Cancer (TNBC) is breast cancer subtype with negative expression of estrogen, progesterone, and Human Epidermal Growth Factor Receptor-2.¹ TNBC accounts for 15-20% of all breast carcinomas.²  TNBC neoplasms are often aggressive¹ and highly heterogenous.² Unlike for other breast cancer subtypes, there is a lack of effective targeted therapies.² Germline variants in tumor suppression genes have been shown to increase the risk of developing TNBC³ which suggests that cyclin dependent kinase (CDK) inhibitors in combination with other therapies, such as PI3K pathway inhibitors, may play a promising role treating TNBC. Methods: Studies were performed in vitro, using breast cancer cell lines, and in vivo, using mouse models. TNBC cell lines were treated with palbociclib, a CDK 4/6 inhibitor, and NVP-BEZ235, NVP-BYL719, or NVP-BKM120, PI3K pathway inhibitors.⁴ Glucose uptake/ consumption, cell proliferation, cell death, and cell cycle stage were analyzed.⁴ TNBC cell lines were also treated with Alpelisib, a PI3K pathway inhibitor,  Ribociclib, a CDK 4/6 inhibitor, and Palbociclib, a CDK 4/6 inhibitor to define the relationship between combination CDK 4/6 inhibitor and PI3K inhibitor therapy.⁵ Mouse models were used to test drug synergy in vivo.⁵ Results: CDK 4/6 inhibitors on their own can upregulate AKT and mTOR levels.⁴ Overexpression of AKT and mTOR promotes cell growth. Combination therapy of CDK 4/6 inhibitors and PI3K pathway inhibitors synergistically enhances downregulation of the PI3K pathway and phosphorylation of the retinoblastoma (Rb) protein, contributing to increased cell growth arrest and apoptosis.⁴ However, the synergistic relationship may be dependent on tumor cells having a wildtype Rb 1 gene.⁵ The relationship between CDK 4/6 inhibitors and PI3K pathway inhibitors in TNBC cells lacking wildtype Rb 1 genes has been shown to be antagonistic.⁵ The observed synergistic effect between CDK 4/6 inhibitors and PI3K pathway inhibitors extends to enhanced antigen presentation and activation of cytotoxic T cells.⁵ Additionally this combination therapy downregulated glucose uptake and consumption.⁴ Conclusions: The synergistic effect of combination CDK 4/6 inhibitor and PI3K inhibitor therapy on enhancing cell growth arrest and death, downregulation of glucose uptake, and anti-tumor immunogenicity is promising. Dependence on Rb status requires greater evaluation prior to clinical translation. Overall, these findings above show strong support for further investigation of combination CDK 4/6 inhibitors and PI3K inhibitors in TNBC.

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