Decreased ER dependency after acquired resistance to CDK4/6 inhibitors

Abstract

Background

Cyclin-dependent kinase (CDK) 4/6 inhibitors represent a significant advancement in the treatment of estrogen receptor (ER)-positive human epidermal growth factor receptor 2-negative advanced breast cancer. However, mechanisms of alterations after acquired resistance to CDK4/6 inhibitors and the optimal treatment options are still not established.

Methods

Abemaciclib-resistant cell lines were established from the models of estrogen deprivation-resistant cell lines which retained ER expression and activated ER function derived from MCF-7 breast cancer cell lines. Ribocilib-resistant cell lines were established in the same method as previously reported.

Results

Both abemaciclib- and ribociclib-resistant cell lines showed decreased ER expression. ER transcriptional activity was maintained in these cell lines; however, the sensitivity to 4-hydroxytamoxifen and fulvestrant was almost completely lost. These cell lines did not exhibit any ERα gene mutation. Abemaciclib-resistant cell lines demonstrated low sensitivity to other CDK4/6 inhibitors; sensitivities to PI3K inhibitor, mTOR inhibitor, and chemotherapeutic drugs were maintained.

Conclusions

Dependence on ER signaling appears to decrease after the development of acquired resistance to CDK4/6 inhibitors. Further, CDK4/6 inhibitor-resistant cells acquired cross-resistance to other CDK4/6 inhibitors, PI3K/Akt/mTOR inhibitor therapy and chemotherapeutic drugs might serve as optimal treatment options for such breast cancers.

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Funding

This study was funded in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, Science and Technology of Japan, a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan, the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO), and a grant from the Smoking Research Foundation.

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Correspondence to Masafumi Iida.

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Shin-ichi Hayashi received research grants from Novartis Pharma K.K and Astra Zeneca K.K.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Iida, M., Toyosawa, D., Nakamura, M. et al. Decreased ER dependency after acquired resistance to CDK4/6 inhibitors. Breast Cancer 27, 963–972 (2020). https://doi.org/10.1007/s12282-020-01090-3

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Keywords

  • Breast cancer
  • CDK4/6 inhibitor
  • Abemaciclib
  • Estrogen receptor
  • Resistance