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Resistance Mechanisms to Cyclin-Dependent Kinase Inhibitors

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Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((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.

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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

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  1. Women’s Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Wolf Ruprecht Wiedemeyer

  2. AbbVie-Stemcentrx, 450 E. Jamie Court, South San Francisco, CA, 94080, USA

    Wolf Ruprecht Wiedemeyer

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  1. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Yosef Yarden

  2. Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheeva, Israel

    Moshe Elkabets

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Wiedemeyer, W.R. (2018). Resistance Mechanisms to Cyclin-Dependent Kinase Inhibitors. In: Yarden, Y., Elkabets, M. (eds) Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways. Resistance to Targeted Anti-Cancer Therapeutics, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-67932-7_8

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