Open AccessMathematical modelling of breast cancer cells in response to endocrine therapy and Cdk4/6 inhibition
Author(s) -
Wei He,
Diane M. Demas,
Isabel Conde,
Ayesha N. Shajahan-Haq,
William T. Baumann
Publication year - 2020
Publication title -
journal of the royal society interface
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.655
H-Index - 139
eISSN - 1742-5689
pISSN - 1742-5662
DOI - 10.1098/rsif.2020.0339
Subject(s) - fulvestrant , palbociclib , breast cancer , aromatase , aromatase inhibitor , estrogen receptor , cancer research , cancer , cell growth , medicine , pharmacology , oncology , metastatic breast cancer , biology , biochemistry
Oestrogen receptor (ER)-positive breast cancer is responsive to a number of targeted therapies used clinically. Unfortunately, the continuous application of any targeted therapy often results in resistance to the therapy. Our ultimate goal is to use mathematical modelling to optimize alternating therapies that not only decrease proliferation but also stave off resistance. Toward this end, we measured levels of key proteins and proliferation over a 7-day time course in ER+ MCF-7 breast cancer cells. Treatments included endocrine therapy, either oestrogen deprivation, which mimics the effects of an aromatase inhibitor, or fulvestrant, an ER degrader. These data were used to calibrate a mathematical model based on key interactions between ER signalling and the cell cycle. We show that the calibrated model is capable of predicting the combination treatment of fulvestrant and oestrogen deprivation. Further, we show that we can add a new drug, palbociclib, to the model by measuring only two key proteins, cMyc and hyperphosphorylated RB1, and adjusting only parameters associated with the drug. The model is then able to predict the combination treatment of oestrogen deprivation and palbociclib. We illustrate the model's potential to explore protocols that limit proliferation and hold off resistance by not depending on any one therapy.