Targeting CDK2 for cancer therapy

Abstract

Targeting cell-cycle regulatory processes by inhibiting cyclin-dependent kinases (CDKs) has long been considered a significant therapeutic strategy for oncology. Recent studies have highlighted the complexity of targeting CDK2 for cancer therapy. Unlike CDK4/6 inhibitors, CDK2 inhibitors can impact different phases of the cell cycle by modulating distinct effector pathways, and the response to CDK2 inhibitors is controlled by the genetic and epigenetic makeup of the tumor. Biomarkers have emerged that can inform the effective use of these drugs and include cyclin E and p16INK4A. Work across several different tumor types indicates that CDK2 inhibitors can be combined effectively with various drug classes. However, more investigation is needed to understand the potential limitations and drug toxicities of existing CDK2 inhibitors and those in development.

Keywords: CDK inhibitors; CDK2; CDK4/6; CDKN2A; CP: Cancer; RB; cell cycle; cyclin D1; cyclin E; p16IN4A.

Figure 1.. Distinct cell cycles under different conditions

(A) The conventional depiction of the cell cycle with initiation occurring with coordinated phosphorylation of RB and related proteins by CDK4/6 and CDK2 complexes. This event releases E2F activity to promote further activation of CDK2 and progression through G1/S and additional phases of the cell cycle. (B) In the context of resistance to CDK4/6 inhibitors, the activity of CDK2 either in complex with cyclin E or cyclin D1 can bypass the requirement for CDK4 or CDK6 activity. (C) In the context of tumors with high expression of p16INK4A, the transition through G1/S is more dependent on CDK2. This dependence can be apparent in both RB-proficient and RB-deficient tumor models.

Figure 2.. Structural comparison of CDKs bound to type I ATP-competitive inhibitors

(Left) Crystal structure of CDK2 bound to PF-06873600 (PDB: 7kjs). (Middle) Structural model of palbociclib bound to CDK4 created by overlaying the position of the drug in the palbociclib-CDK6 crystal structure (PDB: 5l2i) with the position of CDK4 in the abemaciclib-CDK4-cyclin D3 crystal structure (PDB: 7sj3). One approach to engineering CDK2 potency has been replacement of the palbociclib piperazine-pyridine ring system with a group that contacts CDK2-specific residues near the hinge region of the kinase. For example, the aminopiperidine sulfonamide group in PF-06873600 makes a hydrophobic contact with F82 in the CDK2 hinge, which corresponds to H95 in CDK4, and forms a hydrogen bond with K89 in the CDK2 helix proximal to the hinge (T102 in CDK4). (Right) Structural overlay of PF-06873600 and CDK1 in the CDK1-cyclin B-Cks2 crystal structure (PDB: 4yc3). Notably, all the sidechains around the ATP binding pocket are identical in CDK1 and CDK2, so the origins of the modest selectivity of this compound and other CDK2 specific inhibitors remain uncertain.

Figure 3.. Distinct mechanisms through which CDK2 catalytic inhibitors can suppress cell cycle progression

(A) (Left) In tumors that express high levels of p16INK4A and cyclin E, the catalytic inhibitors prevent the phosphorylation of substrates including RB and nucleolin and suppress the phosphorylation of sensors for CDK activity. These molecular events lead to the repression of E2F and suppression of cyclin A, which are associated with a G1 arrest. (Right) In tumors that do not express p16INK4A, the treatment with catalytic CDK2 inhibitors does not inhibit RB phosphorylation or other molecular events. In this condition, the catalytic inhibitor induces an enrichment of cells with a 4N DNA content. The inclusion of a CDK4/6 inhibitor with the CDK2 catalytic inhibitor can phenocopy features of p16INK4A expression and lead to RB dephosphorylation and other molecular effects. (B) Comparison between genetic depletion and catalytic inhibition of CDK2. While many cells tolerate CDK2 depletion by relying on cyclin A/CDK1 for G2/M progression, catalytic inhibitors maintain inactive CDK2-cyclin complexes, resulting in the accumulation of cells with 4N DNA content. The exact nature of this arrest remains under investigation and could be related to multiple functions of CDK2 in cell biology.