For example, resistance to ET has been associated with dysregulation of the CDK4-Rb-E2F transcriptional axis [16]; the CDK4/6 inhibitor palbociclib was shown to decrease the expression of estrogen-regulated genes and reduce sensitivity to ET [17]; resistance to ET and CDK4/6 inhibitors was linked to increased activation of the PAM pathway [18,19]; PI3K inhibition was reported to increase ER transcriptional function [20]; and BC cells resistant to PI3K inhibitors were shown to have sustained CDK4/6 activity [21]. The gene discussed is RB1; the disease is breast cancer.