Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

Abstract

A hallmark of cancer is the deregulation of cell-cycle machinery, ultimately facilitating aberrant proliferation that fuels tumorigenesis and disease progression. Particularly, in breast cancers, cyclin D1 has a crucial role in the development of disease. Recently, a highly specific inhibitor of CDK4/6 activity (PD-0332991) has been developed that may have efficacy in the treatment of breast cancer. To interrogate the utility of PD-0332991 in treating breast cancers, therapeutic response was evaluated on a panel of breast cancer cell lines. These analyses showed that the chronic loss of Rb is specifically associated with evolution to a CDK4/6-independent state and, ultimately, resistance to PD-0332991. However, to interrogate the functional consequence of Rb directly, knockdown experiments were performed in models that represent immortalized mammary epithelia and multiple subtypes of breast cancer. These studies showed a highly specific role for Rb in mediating the response to CDK4/6 inhibition that was dependent on transcriptional repression manifest through E2F, and the ability to attenuate CDK2 activity. Acquired resistance to PD-03322991 was specifically associated with attenuation of CDK2 inhibitors, indicating that redundancy in CDK functions represents a determinant of therapeutic failure. Despite these caveats, in specific models, PD-0332991 was a particularly effective therapy, which induced Rb-dependent cytostasis. Combined, these findings indicate the critical importance of fully understanding cell-cycle regulatory pathways in directing the utilization of CDK inhibitors in the clinic.

Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors

“…While these results combined with previously published preclinical studies demonstrate a clear acute cytostatic response, prior studies have also described the ability of extended CDK4/6 inhibition to drive increased rates of cellular senescence, or permanent cell cycle exit, while not increasing rates of apoptosis. 13 Such results demonstrate a sustained/durable cytostatic response, which has also been observed in clinical trials examining the efficacy of PD-0332991. Specifically, one such study examining the effectiveness of CDK4/6 inhibition among a population of teratoma patients demonstrated continued efficacy (delayed disease progression) over a period of two years.…”

“…To specifically interrogate this concept, explants were treated with the CDK4/6 inhibitor PD-0332991, a potent cytostatic agent that is in phase II clinical trials for multiple malignancies, including breast cancer. [11][12][13] Treatment with PD-0332991 revealed highly profound suppression of Ki67 staining. This effect was specific to the drug and was not observed in tissues treated with DMSO (vehicle) for the same time period (Fig.…”

“…11,12,14 RB is the proto-typical tumor suppressor that functions downstream of CDK4/6 to modulate cell cycle progression. [15][16][17] Tumors that are RB-deficient express exceedingly high levels of p16ink4a.…”

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

“…Importantly, although the possibility remains, there is no clear evidence that blocking the cells in G1 phase would lead to reduced cisplatin toxicity in cancer cells (66). Another important consideration is that the cell-cycle effects of CDK4/6 inhibitors are completely dependent on functional Rb and the CDK4/6 pathway (14,67). Rb is inactivated in multiple cancers, including in about 90% small-cell lung cancers (11,20,50), which are routinely treated with cisplatin.…”

Cyclin-Dependent Kinases (Cdk) as Targets for Cancer Therapy and Imaging

“…Certainly, selective inactivation of any Cdk would not be as efficient as inhibition of multiple Cdk, including Cdk1, and involves the risk of easy development of Cdk inhibitor resistance, especially by alterations in the primarily targeted pathway. The response on Cdk4 and Cdk6 selective inhibitor PD 0332991 is significantly linked to functional Rb, transcriptional repression through E2F and the ability to attenuate Cdk2 activity, otherwise resistance to PD 0332991 acquired in tumor cell lines (Dean et al, 2010). In contrast, high efficiency of treatment in Cdk4/ Cdk6-dependent tumors and even reversal of resistance to estrogen receptor pathway targeting with tamoxifen by combined therapy with PD 0332991 could be achieved (Finn et al, 2009).…”