Holly Hodge

Background: Breast cancer has continued to increase in incidence and now accounts for 31% of all cancer diagnoses¹. Breast cancer is classified into subtypes based on the presence of hormone receptors and the human epidermal growth factor receptor 2 protein¹. Hormone receptor-positive breast cancer is the most common subtype, accounting for 75% of all breast cancer cases¹. Treatment varies based on the stage and subtype, and includes surgery, chemotherapy, endocrine therapy, and targeted drug therapy². One combination therapy that can be used for patients with estrogen receptor-positive metastatic breast cancer is a combination of endocrine therapy and a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor³. Unfortunately, a subgroup of patients develop resistance to this combination therapy and subsequently experience disease progression³. For this subgroup of patients, alternative clinical strategies are needed to treat these resistant cancers³.

Objective: In this narrative review, we explored the role of the PI3K/AKT/mTOR pathway in resistance to endocrine therapy and CDK4/6 inhibitors as well as targeting this pathway to overcome resistance.

Search Methods: An online search utilizing PubMed’s database was performed using the following keywords: “breast cancer,” “endocrine therapy,” “CDK4/6 inhibitors,” and “PI3K/AKT/mTOR pathway,” with the publication year being restricted from 2018 to 2023.

Results: The upregulation and mutation of proteins in the PI3K/AKT/mTOR pathway were found in patients that experienced disease progression on endocrine therapy and CDK4/6 inhibitors³. In cell lines resistant to endocrine therapy and CDK4/6 inhibitors, a mTOR inhibitor alone as well as a triple combination therapy of an mTOR inhibitor, endocrine therapy, and CDK4/6 inhibitor were shown to promote tumor regression⁴. In a mouse model, a triple combination of an AKT inhibitor, endocrine therapy, and a CDK4/6 inhibitor was shown to be effective in mice resistant to endocrine therapy and CDK4/6 inhibitors, causing increased apoptosis and reactive fibrosis, as well as full inhibition of tumor growth after eight weeks of treatment⁵. In addition, another resistant mouse model showed that a triple combination therapy of a PI3K inhibitor, endocrine therapy, and CDK4/6 inhibitor not only inhibited tumor growth but also caused tumor regression⁶. In a phase I/II clinical trial, a triple combination therapy of an mTOR inhibitor, endocrine therapy, and a CDK4/6 inhibitor was evaluated for safety in patients with metastatic breast cancer⁷. Common side effects included neutropenia, stomatitis, nausea, and diarrhea⁷. No grade 3/4 QT interval prolongation occurred, indicating cardiac safety, and overall, the triple combination therapy was found to be safe and well-tolerated⁷.

Conclusion: Studies indicate that the PI3K/AKT/mTOR pathway is involved in resistance to endocrine therapy and CDK4/6 inhibitors in metastatic breast cancer. Targeting this pathway through a triple combination therapy of either a PI3K, AKT, or mTOR inhibitor in addition to endocrine therapy and a CDK4/6 inhibitor is effective in inhibiting tumor growth in both resistant cell lines and resistant mice models. This triple combination therapy was found to be safe and tolerable in patients. Inhibiting the PI3K/AKT/mTOR pathway in addition to endocrine therapy and CDK4/6 inhibitors could be a promising treatment, and a phase III clinical trial needs to be performed to determine the efficacy of the triple combination therapy in comparison to other therapies in patients.

Works Cited:

1. Huang J, Zheng L, Sun Z, Li J. CDK4/6 inhibitor resistance mechanisms and treatment strategies (Review). Int J Mol Med. 2022;50(4):128. doi:10.3892/ijmm.2022.5184
2. Bhushan A, Gonsalves A, Menon JU. Current State of Breast Cancer Diagnosis, Treatment, and Theranostics. Pharmaceutics. 2021;13(5):723. Published 2021 May 14. doi:10.3390/pharmaceutics13050723
3. Abu-Khalaf MM, Alex Hodge K, Hatzis C, et al. AKT/mTOR signaling modulates resistance to endocrine therapy and CDK4/6 inhibition in metastatic breast cancers. NPJ Precis Oncol. 2023;7(1):18. Published 2023 Feb 16. doi:10.1038/s41698-023-00360-5
4. Rodriguez MJ, Perrone MC, Riggio M, et al. Targeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer models. Sci Rep. 2023;13(1):2710. Published 2023 Feb 15. doi:10.1038/s41598-023-29425-y
5. Alves CL, Ehmsen S, Terp MG, et al. Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer [published correction appears in Nat Commun. 2021 Sep 16;12(1):5588]. Nat Commun. 2021;12(1):5112. Published 2021 Aug 25. doi:10.1038/s41467-021-25422-9
6. O’Brien NA, McDermott MSJ, Conklin D, et al. Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer. Breast Cancer Res. 2020;22(1):89. Published 2020 Aug 14. doi:10.1186/s13058-020-01320-8
7. Bardia A, Hurvitz SA, DeMichele A, et al. Phase I/II Trial of Exemestane, Ribociclib, and Everolimus in Women with HR⁺/HER2^– Advanced Breast Cancer after Progression on CDK4/6 Inhibitors (TRINITI-1). Clin Cancer Res. 2021;27(15):4177-4185. doi:10.1158/1078-0432.CCR-20-2114