Journal
BREAST CANCER
Volume 27, Issue 5, Pages 963-972Publisher
SPRINGER JAPAN KK
DOI: 10.1007/s12282-020-01090-3
Keywords
Breast cancer; CDK4; 6 inhibitor; Abemaciclib; Estrogen receptor; Resistance
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Funding
- Ministry of Education, Science, Sports, Science and Technology of Japan
- Ministry of Health, Labor and Welfare of Japan
- Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO)
- Smoking Research Foundation
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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 ER alpha 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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