Abstract 3344
Background
CDK4/6 inhibitors have been widely used around the world for advanced estrogen receptor positive breast cancer patients in the past several years. However, the benefit offered by CDK4/6 inhibitors is individually different, therefore it is imperative need to identify the biomarker and/or monitoring marker.
Methods
We established CDK6 over expression cell lines (MCF7-C6) from MCF-7 by stably transfected CDK6 expression vector. We also established Ribociclib-resistant cell lines (RIBR) after long-term culture under the condition of sufficient doses of Ribociclib from estrogen deprivation-resistant cell lines (EDR) which established from MCF-7 cultured with steroid depleted medium as aromatase inhibitor resistance models. We further established RIBR(-R) cell lines from RIBR by long-term cultured without Ribociclib.
Results
First, we assessed IC50 of Ribociclib in several cell lines. Luminal cell lines exhibited lower Ribociclib IC50 than non-luminal cell lines. Immunoblot analysis of Luminal cell lines showed extremely lower levels of CDK6 compared with others. Then we established MCF7-C6. MCF7-C6 reduced Ribociclib sensitivity equivalent to non-luminal cell lines. Next, we established RIBR to understand the characteristics in acquired resistance. We confirmed RIBR showed higher Ribociclib IC50 than EDR. Surprisingly the expression levels of CDK6 were not reduced in RIBR, indicating that the mechanism of resistance to Ribociclib would be different between MCF-7-C6 and RIBR. Then, we explored the efficacy of other CDK4/6 inhibitors on MCF7-C6 and RIBR. MCF7-C6 and RIBR cells showed cross-resistant not only to Palbociclib but Abemaciclib. The expression levels of p21 were reduced in both cell lines though the mechanisms of resistance to CDK4/6 inhibitors were different. Finally, we established RIBR(-R). RIBR(-R) showed more sensitive to Ribociclib than RIBR. In addition, p21 levels of RIBR(-R) were restored to the same degree as EDR.
Conclusions
Ribociclib sensitivity was proportional to the expression levels of p21, suggesting that p21 levels might be the monitoring marker for the CDK4/6 inhibitors resistance in breast cancer.
Clinical trial identification
Legal entity responsible for the study
Shin-ichi Hayashi.
Funding
Grant-in-aid for scientific research from the Ministry of Education, Science, Sports, Science and Technology of Japan; Grant-in-aid for cancer research from the Ministry of Health, Labour and Welfare of Japan; Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO); Grant from the Smoking Research Foundation.
Editorial Acknowledgement
Disclosure
S-I. Hayashi: Research grants: Novartis Pharma K.K, AstraZeneca K.K. All other authors have declared no conflicts of interest.
Resources from the same session
1159 - Molecular characterization and search for founding effects in Canarian families with Hereditary Breast and Ovarian Cancer Syndrome
Presenter: Elisenda Llabres Valenti
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
3725 - Effect of the polymorphism rs2066844 of the NOD2 gene on colon cancer incidence in a high cardiovascular risk population. Modulation by gender
Presenter: Judith Begona Ramirez Sabio
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
3708 - Effect of the polymorphisms rs1476413, rs1801131, rs4846052 and rs6541003 of the MTHFR gene on prostate cancer in a high cardiovascular risk population
Presenter: Judith Begona Ramirez Sabio
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
5057 - Association of a genetic variant in cyclin-dependent kinase Inhibitor 2A gene with the increased risk of breast cancer
Presenter: Soodabeh Shahid Sales
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
5970 - Investigating the role of HAT protein TIP60 in regulating functional dynamics of nuclear receptor PXR
Presenter: KARISHMA BAKSHI
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1360 - The role of downregulated SIRT3 expression in patients with hepatocellular carcinoma
Presenter: Hanhee Jo
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1634 - Prediction and Intervention of Colorectal Cancer Risk with Artificial Intelligent System
Presenter: Yang Ge
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
4921 - Measuring the Efficiency of Cancer Care in Europe
Presenter: Rikard Althin
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1235 - Circulating cell-free DNA isolated from plasma of mesenteric veins predicts prognosis in stage II colorectal cancer patients
Presenter: Chih-Yung Yang
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
5169 - _lonality of uterine carcinosarcoma as a factor of clinical prognosis.
Presenter: Natalia Levitskaya
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract