Megan Foster

 Background:  There are over 200,000 cases of BC diagnosed a year in the US, and for a woman, there is a 1/8 chance of being diagnosed with breast cancer in their lifetime. ER+ (Estrogen Receptor positive) breast cancer can be fairly common among women, as it is the most common malignancy of women in the US after skin cancer and 75% of breast cancers are ER+. A viable treatment for ER+ Breast cancer is the use of CDK4/6 inhibitors that arrest the cell cycle at G0/G1 phases by dephosphorylating Rb. CDK4/6 inhibitors, like Palbociclib, go beyond their recognized function by further inducing some genes that are associated with cell growth, yielding mitogenic pathways that can be aberrant, acquire mutations, and lead to resistance. Combination therapies are being implemented to overcome this resistance and improve outcomes. Resistance is common in prolonged treatment and may require coregulators like ERX-11, a deregulation of mTOR, or increased p27 proteins in cells to achieve a prolonged and greater efficacy. However, there is a knowledge gap for the best standardized treatment and a clinical need to obtain the best drug sequence for the optimal clinical outcomes.

Objective(s): In this review, we explored the mechanisms of combination therapy with CDK4/6 inhibitors in overcoming resistance and assessing the clinical outcomes and treatment for ER+ Breast Cancer.

Search Methods: The PubMed database was used in an online search from 2017-2023 using the keywords: “CDK4/6 Inhibitors”, “ER+ Breast Cancer”, “Resistance”, and “Cell Cycle”.

Results: Studies showed that the CDK4/6 inhibitor Palbociclib, worked through inhibition of the ER pathway and the cyclin D-CDK4/6-E2F pathways and  synergistically induced cell senescence in ER (+) breast cancer. However, a large number of genes that are downstream from mitogenic signaling (e.g. FOS, EGR1, JUN, DUSP6) were induced as a consequence of this treatment. This signaling is not just a feature of cell cycle inhibition, since endocrine therapy did not induce these genes, suggesting CDK4/6 inhibitors induces a mitogenic response. This shifted the focus of research to discover new therapeutic approaches that overcome resistance to CDK4/6 inhibitors. Endocrine therapy-resistant tumors retain ER signaling through oncogenic coregulator proteins, therefore, combination of ERX- 11, that binds to the estrogen receptor (ER) and modulates ER-coregulator interactions, with CDK4/6 inhibitors was found to be synergistic in decreasing the proliferation of both endocrine therapy-sensitive and resistance cell lines, in vitro and in vivo. Furthermore, it was found that sustained activity of mTORC1 in CAMA1 lines promotes complete senescence and suggests strategy for new drug combination with Palbociclib as senescence is generally regarded as a tumor suppressive process.

Conclusion: CDK4/6 inhibitors are a promising treatment for ER+ Breast Cancer, as they are able inhibit cell cycle progression by dephosphorylating Rb. However, this mechanism can rapidly accumulate mutations and cause resistance, making this an important area of growing research. Combination treatments currently show a promising pathway in overcoming this resistance by targeting different courses of resistance to improve clinical outcomes.

Works Cited:

1.  Kishino E, Ogata R, Saitoh W, et al. Anti-cell growth and anti-cancer stem cell activity of the CDK4/6 inhibitor Palbociclib in breast cancer cells. Breast Cancer. 2020;27(3):415-425. doi:10.1007/s12282-019-01035-5
2. Kumarasamy V, Vail P, Nambiar R, Witkiewicz AK, Knudsen ES. Functional Determinants of Cell Cycle Plasticity and Sensitivity to CDK4/6 Inhibition. Cancer Res. 2021;81(5):1347-1360. doi:10.1158/0008-5472.CAN-20-2275
3. SaatciO,Huynh-DamKT,SahinO.Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies. J Mol Med (Berl). 2021;99(12):1691-1710. doi:10.1007/s00109-021-02136-5 https://link-springer-com.srv-proxy2.library.tamu.edu/content/pdf/10.1007/ s00109-021-02136-5.pdf
4. Viswanadhapalli S, Ma S, Sareddy GR, et al. Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers. Breast Cancer Res. 2019;21(1):150. Published 2019 Dec 26. doi:10.1186/s13058-019-1227-8
5. Maskey RS, Wang F, Lehman E, et al. Sustained mTORC1 activity during Palbociclib-induced growth arrest triggers senescence in ER+ breast cancer cells. Cell Cycle. 2021;20(1):65-80. doi:10.1080/15384101.2020.1859195
6. Knudsen ES, Witkiewicz AK. Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer. Oncotarget. 2016;7(43):69111-69123. doi:10.18632/oncotarget.11588
7. Li Y, Brown PH. Prevention of ER-negative breast cancer. Recent Results Cancer Res. 2009;181:121-134. doi:10.1007/978-3-540-69297-3_13 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068124/
8. HankerAB,SudhanDR,ArteagaCL.OvercomingEndocrineResistancein Breast Cancer. Cancer Cell. 2020;37(4):496-513. doi:10.1016/j.ccell.2020.03.009 https://www.cell.com/cancer-cell/pdf/S1535-6108(20)30149-5.pdf
9. McAndrewNP,FinnRS.ManagementofERpositivemetastaticbreastcancer. Semin Oncol. 2020;47(5):270-277. doi:10.1053/j.seminoncol.2020.07.005 https://www-clinicalkey-com.srv-proxy2.library.tamu.edu/#!/content/playContent/ 1-s2.0-S0093775420300828?returnurl=null&referrer=null