Selective inhibitors of CDK4/6 were recently approved by the FDA for use in combination with endocrine therapy (ET), and represent the new standard of care.¹ However, some patients do not respond or develop resistance to these treatments, and therapies are required in this setting. Although data are emerging on the mechanisms of intrinsic insensitivity to CDK4/6 inhibitors as monotherapies, which include cyclin E1 amplification, CDK6 amplification, and Rb deletion, little data exist on mechanisms of resistance to combined ET and CDK4/6 inhibition.

The authors established MCF-7 cell line and patient-derived xenograft (PDX) models that are resistant to combined ET and the CDK4/6 inhibitor palbociclib through long-term culture, allowing them to better understand mechanisms underlying CDK4/6 inhibitor resistance and to model therapeutic strategies in this setting. They also evaluated a therapeutic strategy in vitro and in vivo using MCF cell lines that are resistant to ET, and in an estrogen receptor–positive PDX model derived from a patient who progressed while receiving ET.²

Cells resistant to CDK4/6 inhibitors alone and in combination with ET show disrupted senescent pathways, and insensitivity to the induction of senescence. MDM2 inhibitors induce cells to enter senescence, and consequently the use of a new-generation MDM2 inhibitor (CGM097)—either in combination with CDK4/6 inhibitor treatment, or following acquisition of CDK4/6 inhibitor resistance—is being investigated. CGM097 was evaluated either in combination with CDK4/6 inhibitor treatment, or in combination with fulvestrant following acquisition of CDK4/6 inhibitor resistance. CGM097 was effective alone or in combination with fulvestrant in CDK4/6 inhibitor‒resistant cells in vitro and in vivo, and resulted in a loss of G1 cells and a reduction in beta-galactosidase, a marker of senescence.

Another mechanism of CDK4/6 inhibitor resistance that has been identified is CDK2 activation, which can occur through cyclin E amplification. As a second therapeutic strategy, a panel of pan-CDK inhibitors with CDK2 activity was screened in resistant lines, and CYC065 (Cyclacel), a highly selective CDK2/9 inhibitor, was identified as having the most durable response and highest synergy with ET in long-term culture. The combined resistant models were sensitive to CYC065 in vitro and in vivo. CYC065 was mechanistically distinct from CDK4/6 inhibitors as it caused arrest in a different phase of the cell cycle and affected expression of different cell-cycle proteins.

The authors concluded that an underlying mechanism of combined ET and CDK4/6 inhibitor resistance is senescent escape, which allows for normal proliferation upon removal of the drug. Using in vitro and in vivo models of combined ET and CDK4/6 inhibitor resistance, 2 novel therapeutic strategies have been identified for hormone receptor–positive breast cancer, which represents the next clinical challenge in this disease as the natural history of the disease is changed with the increasing use of CDK4/6 inhibitors.

References

1. Zardavas D, et al. Expert Opin Investig Drugs. 2017;26:1357-1372.
2. Lim E, et al. SABCS 2017. Abstract P4-04-12.