Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer

Abstract

Pharmacological inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are now an established standard of care for patients with advanced hormone receptor-positive breast cancer. The canonical mechanism underlying CDK4/6 inhibitor activity is the suppression of phosphorylation of the retinoblastoma tumor suppressor protein, which serves to prevent cancer cell proliferation. Recent data suggest that these agents induce other diverse effects within both tumor and stromal compartments, which serve to explain aspects of their clinical activity. Here, we review these phenomena and discuss how they might be leveraged in the development of novel CDK4/6 inhibitor-containing combination treatments. We also briefly review the various known mechanisms of acquired resistance in the clinical setting.

Keywords: Breast cancer; CDK4/6; Cell cycle; Combination therapy; Cyclin-dependent kinase; Drug resistance.

Fig. 1

The role of cyclin D and CDK4/6 in cell cycle progression in breast cancer

Fig. 2

Inhibition of G1/S cyclin-dependent kinases by CDK4/6 inhibitors. A The traditional model suggests that CDK4/6 inhibitors inhibit active CDK4/6-cyclin D-p21/p27 holoenzymes, preventing RB phosphorylation by CDK4/6. B Two models suggest mechanisms by which CDK4/6 inhibitors indirectly inhibit CDK2 activity. (I) Guiley et al. propose that CDK4/6 inhibitors bind to monomeric CDK4/6, preventing the formation of CDK4/6-cyclin D-p21/p27 trimers. The free p21 then binds to and inhibits cyclin E/CDK2, preventing RB phosphorylation. This model suggests that the CDK4/6i induces cell cycle arrest through an indirect inhibition of CDK2, rather than inhibition of CDK4/6 activity. (II) Pack et al. propose that CDK4/6i inhibitors do inhibit CDK4/6 catalytic activity directly, but also displace p21 from established CDK4-cyclin D-p21 trimers, again leading to indirect inhibition of cyclin E/CDK2