The evolution of cyclin dependent kinase inhibitors in the treatment of cancer

ABSTRACT

Introduction: The cell cycle cyclin-dependent kinases (CDKs) play a critical role in controlling the transition between cell cycle phases, as well as cellular transcription. Aberrant CDK activation is common in cancer, and deregulation of the cell cycle a key hallmark of cancer. Although CDK4/6 inhibitors are now a standard-of-care option for first- and second-line HR+/HER2- metastatic breast cancer, resistance inevitably limits their clinical benefit.

Areas covered: Early pan-CDK inhibitors targeted the cell cycle and RNA polymerase II phosphorylation, but were complicated by toxicity, providing a rationale and need for the development of selective CDK inhibitors. In this review, we highlight selected recent literature to provide a narrative review summarizing the current CDK inhibitor therapeutic landscape. We detail the challenges associated with targeting CDKs for the treatment of breast and other cancers and review emerging biomarkers that may aid response prediction. We also discuss the risk-benefit ratio for CDK therapy and explore promising combination approaches.

Expert opinion: Although CDK inhibitors may stem the proliferation of cancer cells, resistance remains an issue, and currently there are limited biomarkers to predict response to therapy. Ongoing research investigating CDK inhibitors in cancer is of paramount importance to define appropriate and effective treatment regimens.

KEYWORDS:

• Breast
• biomarkers
• cancer
• cell cycle
• cyclin dependent kinase inhibitor
• oncology
• resistance

Article highlights

• Aberrant CDK activation is common in cancer, and deregulation of the cell cycle is one of the key hallmarks of cancer

• Early pan-CDK inhibitors targeted both the cell cycle and RNA polymerase II phosphorylation, but such approaches were complicated by toxicity, providing a rationale for exploring the utility of selective CDK inhibitors

• Although small-molecule inhibitors of CDK4/6 are now established as a standard-of-care therapeutic option for first- and second-line HR+/HER2- metastatic breast cancer, resistance remains an issue

• Selective CDK inhibitors are in development for a range of cancer indications, including further options for breast cancer with molecules that target other distinct CDKs in addition to or instead of CDK4/6

• Drug resistance is complex, the known resistance mechanisms to the approved CDK4/6 inhibitors are varied, and it is unclear which biomarkers may robustly predict a lack of response

• The identification of biomarkers measured at baseline or on-treatment that are predictive of response is of key importance for choosing the most appropriate therapy, and further research in this area is warranted

• Identifying novel agents and/or appropriate combination approaches involving CDK inhibitors are required to improve efficacy, reduce toxicities, and overcome resistance

Acknowledgments

We thank Janeen Azare PhD, Pfizer, for reviewing manuscript content.

Declaration of interest

K Jhaveri has served as a consultant and on the advisory boards for Novartis, Spectrum Pharmaceuticals, ADC Therapeutics, Pfizer, BMS, Jounce Therapeutics, Taiho Oncology, Genentech, Synthon, AbbVie, AstraZeneca, Lilly Pharmaceuticals, Intellisphere, Seattle Genetics, Blueprint Medicines; research funding from Novartis, Clovis Oncology, Genentech, AstraZeneca, ADC Therapeutics, Novita Pharmaceuticals, Debio Pharmaceuticals, Pfizer, Lilly Pharmaceuticals, Zymeworks, Immunomedics, Puma Biotechnology.

HA Burris 3^rd has received consulting fees paid to institution from AstraZeneca, FORMA Therapeutics, Celgene, Incyte, research funding paid to institution: Roche/Genentech, Bristol-Myers Squibb, Incyte, AstraZeneca, MedImmune, Macrogenics, Novartis, Boehringer Ingelheim, Lilly, Seattle Genetics, Merck, Agios, Jounce Therapeutics, Moderna Therapeutics, CytomX Therapeutics, GlaxoSmithKline, Verastem, Tesaro, BioMed Valley Discoveries, TG Therapeutics, Vertex, eFFECTOR Therapeutics, Janssen, Gilead Sciences, BioAtla, CicloMed, Harpoon Therapeutics, Arch, Arvinas, Revolution Medicines, Array BioPharma, Bayer, BIND Therapeutics, Kyocera, miRNA Therapeutics, Pfizer, Takeda/Millenium, Foundation Medicine, Expert Testimony for Novartis.

TA Yap has received research support from AstraZeneca, Bayer, Pfizer, Tesaro, Jounce, Lilly, Seattle Genetics, Kyowa, Constellation, and Vertex Pharmaceuticals; consultancies from Aduro, Almac, AstraZeneca, Atrin, Bayer, Bristol-Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, Ignyta, Jansen, Merck, Pfizer, Roche, Seattle Genetics, and Vertex Pharmaceuticals.

E Hamilton has received consulting fees paid to institution only (no personal fees) from Pfizer, Genentech/Roche, Eli Lilly and Company (Lilly), Puma Biotechnology, Daiichi Sankyo, Mersana Therapeutics, Boehringer Ingelheim, AstraZeneca, Novartis, Silverback Therapeutics, and Black Diamond; and research/clinical trial support paid to institution only (no personal fees) from AstraZeneca, Hutchinson MediPharma, OncoMed, MedImmune, StemCentrx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millenium, TapImmune, Cascadian, Lilly, BerGenBio, Medivation, Pfizer, Tesaro, Boehringer Ingelheim, Eisai, H3 Biomedicine, Radius Health, Acerta, Takeda, Macrogenics, AbbVie, Immunomedics, FujiFilm, Effector, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros, Clovis, Cytomx, InventisBio, Deciphera, Unum Therapeutics, Sermonix Pharmaceuticals, Sutro, Aravive, Zenith Epigenetics, Arvinas, Torque, Harpoon, Fochon, Black Diamond, Orinove, Molecular Templates, and Silverback Therapeutics.

HS Rugo has received research support to the University of California San Francisco from Eisai, Genentech, Lilly, MacroGenics, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Immunomedics, Daiichi-Sankyo, Daichi, Sermonix, and Pfizer; has served in a consulting role with Samsung and Puma; and has received travel support from Pfizer, Novartis, AstraZeneca, and Roche.

JW Goldman has received research grants from Pfizer and Lilly, and consultant fees from Pfizer.

S Dann is an employee of Pfizer and holds stock in Pfizer.

F Liu is an employee of Pfizer and holds stock in Pfizer.

GY Wong is a former employee of Pfizer and holds stock in Pfizer; is employee of BeiGene and holds stock in BeiGene.

H Krupka is a former employee of Pfizer and holds stock in Pfizer.

GI Shapiro has received research funding from Lilly, Merck KGaA/EMD-Serono, Merck, and Sierra Oncology; served on advisory boards for Pfizer, Lilly, G1 Therapeutics, Roche, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, and Concarlo Holdings; and holds a patent for ‘Dosage Regimen for Sapacitabine and Seliciclib,’ also issued to Cyclacel Pharmaceuticals, and a pending patent, ‘Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition,’ together with Liam Cornell.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by Pfizer. Medical writing support was provided by David Sunter PhD, CMPP of Engage Medical Affairs and was funded by Pfizer. This work was supported by National Institutes of Health awards P30 CA008748