Targeting CDK4 and CDK6: From Discovery to Therapy

Abstract

Biochemical and genetic characterization of D-type cyclins, their cyclin D-dependent kinases (CDK4 and CDK6), and the polypeptide CDK4/6 inhibitor p16INK4 over two decades ago revealed how mammalian cells regulate entry into the DNA synthetic (S) phase of the cell division cycle in a retinoblastoma protein (RB)-dependent manner. These investigations provided proof-of-principle that CDK4/6 inhibitors, particularly when combined with co-inhibition of allied mitogen-dependent signal transduction pathways, might prove valuable in cancer therapy. FDA-approval of the CDK4/6 inhibitor palbociclib used with the aromatase inhibitor letrozole for breast cancer treatment highlights long sought success. The newest findings herald clinical trials targeting other cancers.

Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth

“…Beyond the requirement for RB expression, additional factors that are considered as potential determinants of extent and duration of tumor response to palbociclib include the expression levels of p16, CDK4, and CDK6 in RB-proficient tumors as well as the expression of additional cell-cycle regulators including cyclin E and p27KIP1, and D-type cyclins. 27 These factors-and others yet to be determined-may contribute to Control vs treatment C vs PB P ¼ .012* P ¼ .004 P ¼ .001 P ¼ .001 C vs RT P ¼ .012* P ¼ .049* P ¼ .005 P < .001 C vs PB -. RT P ¼ .001 P < .001 P < .001 P < .001 C vs PB + RT P < .001 P < .001 P ¼ .001 P < .001 C vs RT -.…”

RB1: a prototype tumor suppressor and an enigma

“…The development of effective inhibitors for Cdk4/6 kinases has been one of the most impactful applications of pRB research (Fry et al 2004; for review, see Sherr et al 2016). Complexes of Cdk4/6 and D-type Cyclins have multiple substrates, but it is clear that pRB is one of their most important targets.…”

Differential impact of RB status on E2F1 reprogramming in human cancer

“…In a large subset of tumors retaining RB expression, alterations in cyclin-CDK pathways serve to inactivate tumor suppressor function. This is achieved either via upregulation of RB-inhibiting cyclin-CDK complex components (e.g., cyclin D1, CDK4, and cyclin E) (11)(12)(13)(14)(15)(16) or through loss of CDK inhibitors such as p16 INK4A and p27 Kip1 , both of which serve as tumor suppressors in their own right through this function (11,(15)(16)(17)(18)(19)(20)(21)(22)(23). Underscoring the importance of RB inactivation in promoting cancer cell phenotypes, CDKs have been identified as therapeutic targets, and clinical trials for CDK inhibitors have shown promise across cancer types (NCT01291017, non-small cell lung carcinoma; NCT00141297, lymphoma; NCT01958021, MONALEESA-2, breast cancer) (11,(24)(25)(26), with palbociclib (CDK4/6 inhibitor)…”

“…While tumor-specific proclivities for favoring RB retention and inactivation via CDKs versus RB loss have long been appreciated (15,16,(28)(29)(30), the underlying basis for selectivity is unknown, and the relative impact on downstream E2F1 signaling and function remains undefined. RB loss is typically achieved through genetic alterations including either genomic deletion and loss of heterozygosity or somatic mutations that generate an unstable protein (8,15,29,30).…”