Molecular Pathways: CDK4 Inhibitors for Cancer Therapy

Abstract

Unrestrained growth is the hallmark of cancer, and disrupted cell-cycle regulation is, therefore, common. CDK4 is the key regulator of the G 1 -S transition. In complex with cyclin D, CDK4 phosphorylates retinoblastoma protein (Rb) and drives cell-cycle progression, a process inhibited by p16. The p16-CDK4-cyclin D-Rb is aberrant in the majority of cancers and is, thus, a logical target for anticancer therapy. Previous attempts to block CDK4 with nonselective cyclin-dependent kinase (CDK) inhibitors led to toxicity and little efficacy. However, the recent development of selective CDK4 inhibitors launched the first successful efforts to target the pathway for cancer therapy. Three oral selective CDK4 inhibitors have entered clinical trials: palbociclib (PD0332991), LEE011, and LY2835219. CDK4 inhibitors have in vitro activity against a broad range of cancers and in patients have shown antitumor activity in breast cancer, lymphoma, sarcoma, and other tumors. Major efforts are under way to develop biomarkers of response, understand potential mechanisms of resistance, and develop rational combinations of CDK4 inhibitors with chemotherapy and other targeted drugs. Clin Cancer Res; 20(13); 3379-83. Ó2014 AACR.

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.…”

“…Frequent genetic or epigenetic changes in mitogenic pathways, CDKs, cyclins, or CDK inhibitors are observed in various human cancers (1,4,11). In particular, the G1/S-regulating CDK4/ 6-cyclin D-inhibitors of CDK4 (INK4)-retinoblastoma (Rb) protein pathway frequently is disrupted in cancer cells (11,14). These observations provided an impetus to develop CDK inhibitors as anticancer drugs.…”

“…However, the earlier class of CDK inhibitors had limited specificity, inadequate clinical activity, poor pharmacokinetic properties, and unacceptable toxicity profiles (10,11,14,15). These disappointing initial efforts now have been followed by the development of the specific CDK4/6 inhibitors palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219), which have demonstrated manageable toxicities, improved pharmacokinetic properties, and impressive antitumor activity, especially in certain forms of breast cancer (14,16). Successful early clinical trials with these three CDK4/6 inhibitors have generated cautious enthusiasm that these drugs may emerge as a new class of anticancer agents (14,17).…”

“…These disappointing initial efforts now have been followed by the development of the specific CDK4/6 inhibitors palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219), which have demonstrated manageable toxicities, improved pharmacokinetic properties, and impressive antitumor activity, especially in certain forms of breast cancer (14,16). Successful early clinical trials with these three CDK4/6 inhibitors have generated cautious enthusiasm that these drugs may emerge as a new class of anticancer agents (14,17). Palbociclib recently was approved by Food and Drug Administration for the treatment of metastatic breast cancer and became the first CDK4/6 inhibitor approved for anticancer therapy (18).…”

“…Although CDK2-inhibiting strategies ameliorate AKI, CDK2-specific inhibitors that can be used clinically are unavailable. On the other hand, three CDK4/6 inhibitors currently are in the late stages of clinical development as anticancer therapeutics and have demonstrated manageable toxicity profiles (14). However, whether the CDK4/6 pathway is activated in renal cells during AKI is unknown.…”