WEE1 inhibition delays resistance to CDK4/6 inhibitor and antiestrogen treatment in ER+ MCF7 cells.

Although endocrine therapies and Cdk4/6 inhibitors have improved outcomes for patients with estrogen receptor positive (ER+ ) breast cancer, continuous application of these drugs often results in resistance. Upregulation of G1 and S phase kinase activities during therapy can allow cancer cells to bypass drug induced cell cycle arrest. We investigated whether inhibiting WEE1, a key G2 checkpoint regulator also involved in G1/S transition, could delay the development of resistance. We treated ER+ MCF7 breast cancer cells with palbociclib alternating with a combination of fulvestrant and WEE1 inhibitor AZD1775 for 12 months. We found that the alternating treatment delayed the development of drug resistance to palbociclib and fulvestrant compared to monotherapies. We developed a mathematical model that can simulate cell proliferation under monotherapy and alternating drug treatments. Finally, we showed that the mathematical model can be used to minimize the number of fulvestrant plus AZD1775 treatment periods while maintaining its efficacy.