Functional Determinants of Cell Cycle Plasticity and Sensitivity to CDK4/6 Inhibition

Abstract

Intrinsic or acquired resistance to clinically approved CDK4/6 inhibitors has emerged as a major obstacle that hinders their utility beyond ER+ breast cancer. In this study, CDK4/6-dependent and -resistant models were employed to identify functional determinants of response to pharmacologic CDK4/6 inhibitors. In all models tested, the activation of RB and inhibition of CDK2 activity emerged as determinants of sensitivity. While depleting CDK4 and 6 was sufficient to limit proliferation in specific resistance settings, RB loss rendered cells completely independent of these kinases. The main downstream target in this context was the activation status of CDK2, which was suppressed with CDK4/6 inhibition in an RB-dependent fashion. Protein levels of p27 were associated with plasticity/rigidity of the cell cycle and correlated with sensitivity to CDK4/6 inhibition. Exogenous overexpression and pharmacologic induction of p27 via inhibition of SKP2 and targeting the MEK/ERK pathway enhanced the cytostatic effect of CDK4/6 inhibitors. Mice bearing ER+ xenografts displayed a durable antitumor response to palbociclib; however, over the course of treatment, few cells retained RB phosphorylation, which was associated with limited p27 protein levels as determined by multispectral imaging. Similarly, combination treatment of palbociclib with a MEK inhibitor in pancreatic cancer PDX models upregulated p27 and further enhanced the in vivo tumor response to palbociclib. Collectively, these results suggest that the cell cycle plasticity, which enables tumor models to evade palbociclib-mediated activation of RB, could be targeted using a clinically applicable CDK2 inhibitor. Significance: This work provides a mechanistic insight toward understanding the functional roles of multiple cell cycle regulators that drive plasticity and sensitivity to CDK4/6 inhibition.

The Cancer SENESCopedia: A delineation of cancer cell senescence

“…This would suggest that the senescence phenotype is less dependent on the trigger and rather dependent on the cell line model. To expand on this, we asked whether the same trend in response to ABT-263 and SASP factors is seen for two other drugs described to induce senescence: (1) doxorubicin, a DNA intercalator and topoisomerase II inhibitor (Chang et al, 1999 ; Gewirtz, Cell Reports 36, 109441, July 27, 2021 Resource ll OPEN ACCESS 1999); and (2) cyclin-dependent kinase (CDK) 2/4/6 inhibitor PF-06873600 (next referred to as PF) (Kumarasamy et al, 2021;Pandey et al, 2020). Four cell line models (A549, HCT116, MCF7, Huh7) were selected based on the cancer type (lung, colon, breast, and liver), response to ABT-263, and expression of IL6.…”

RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma

“…Mechanistically, continuous activation of cell cycle signal is one of the predominant biological characteristics of malignant tumor progression, and anti-tumor drugs based on targeting cell-cycle regulators, such as CDK inhibitors, have been proved to be effective [ 42 , 57 ]. However, inherent or acquired resistance of cancer cells to CDK inhibitors has become a major obstacle to their clinical application [ 58 , 59 ]. Alternative strategies to modulate cell cycle regulators in cancer cells are therefore anticipated.…”

MEX3A knockdown inhibits the tumorigenesis of colorectal cancer via modulating CDK2 expression

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