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Resistance Mechanisms to Cyclin-Dependent Kinase Inhibitors

  • Wolf Ruprecht Wiedemeyer
Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 15)

Abstract

Pharmacological cyclin-dependent kinase inhibitors (CDKi) target a class of kinases (CDKs) that are critical mediators of cell cycle progression. Cell cycle deregulation is a hallmark of cancer, and CDKs have long been considered attractive targets for anti-cancer agents. After initial failures of pan-CDKi in clinical trials, two highly specific CDK4/6 inhibitors, palbociclib and ribociclib, are now FDA-approved in hormone receptor-positive breast cancer and an integral part of the treatment regimen. A third CDK4/6 inhibitor, abemaciclib, has also demonstrated promising clinical activity and has been granted break through status by the FDA. CDK4/6 inhibitors in combination with endocrine therapy significantly improve progression-free survival in patients with estrogen receptor-positive breast cancer. CDK1/2 inhibitors, such as dinaciclib, have also advanced to late-stage clinical trials but have yet to be FDA-approved in human cancers. Preclinical studies are beginning to shed light on inherent and acquired mechanisms of resistance to CDKi. Several cancer-relevant signaling pathways, such as the MAPK and PI3K pathways, drive cell cycle progression and contribute to CDK activity, suggesting that concomitant inhibition of these pathways may delay the outgrowth of CDKi-resistant cells. Mutation or deletion of RB1 is associated with inherent resistance to CDK4/6 inhibitors and may also play a role in acquired CDKi resistance. Similarly, amplification or overexpression of cyclin E1 may render cancer cells less dependent on CDK4/6. Ultimately, putative mechanisms of CDKi resistance will need to be validated by the analysis of clinical samples from CDKi-treated cancers.

Keywords

Cyclin-dependent kinase 4 and 6 Drug resistance Receptor tyrosine kinase 

Abbreviations

BLBC

Basal-like breast cancer

CAK

CDK activating kinase

CCND1

Cyclin D1

CCNE1

Cyclin E1

CDK

Cyclin-dependent kinase

CDKi

Cyclin-dependent kinase inhibitor

CIP

CDK interacting protein

ER

Estrogen receptor

ERBB2

Human epidermal growth factor receptor 2 (HER2)

FDA

Federal Drug Administration

HGSC

High-grade serous ovarian cancer

IGFR1

Insulin-like growth factor 1 receptor

INK4

Inhibitor of Cyclin-Dependent Kinase 4

KIP

Kinase interacting protein

NTRK1

Neurotrophic tyrosine kinase receptor type 1 (TrkA)

PDX

Patient-derived xenograft

PI3K

Phosphatidylinositol-3-Kinase

RB1

Retinoblastoma 1

RTK

Receptor tyrosine kinase

SERD

Selective estrogen receptor degrader

TCGA

The Cancer Genome Atlas

Notes

Conflict of Interest

No potential conflicts of interest were disclosed.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Women’s Cancer Program, Cedars-Sinai Medical CenterLos AngelesUSA
  2. 2.AbbVie-StemcentrxSouth San FranciscoUSA

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