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Arrested Developments: CDK4/6 Inhibitor Resistance and Alterations in the Tumor Immune Microenvironment.

ABSTRACT: The uncontrolled proliferation of cancer cells has led to the development of small-molecule inhibitors to target cell-cycle progression. Palbociclib, ribociclib, and abemaciclib are ATP-competitive inhibitors of cyclin-dependent kinases 4/6 (CDK4/6), which function early within the G1 phase of the cell cycle. Recently, CDK4/6 inhibitors have gained FDA approval in postmenopausal estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer and testing in other cancer types is underway. However, resistance to CDK4/6 inhibitors frequently develops. In addition, targeting CDK4/6 may augment the action of immune checkpoint blockade agents. Here, we review recent studies that provide the preclinical rationale for treatment combinations and schedules that include CDK4/6 inhibitors. Furthermore, we discuss inhibitor effects on tumor-infiltrating lymphocytes as a preclinical rationale for targeting CDK4/6 in combination with anti-PD-1 or anti-CTLA-4 antibodies.

SUBMITTER: Teh JLF

PROVIDER: S-EPMC6359975 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Arrested Developments: CDK4/6 Inhibitor Resistance and Alterations in the Tumor Immune Microenvironment.

Teh Jessica L F JLF Aplin Andrew E AE

Clinical cancer research : an official journal of the American Association for Cancer Research 20181004 3

The uncontrolled proliferation of cancer cells has led to the development of small-molecule inhibitors to target cell-cycle progression. Palbociclib, ribociclib, and abemaciclib are ATP-competitive inhibitors of cyclin-dependent kinases 4/6 (CDK4/6), which function early within the G<sub>1</sub> phase of the cell cycle. Recently, CDK4/6 inhibitors have gained FDA approval in postmenopausal estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer and ...[more]

PMID: 30287548

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Project description:Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.

Project description:BackgroundCyclin-dependent kinases (CDKs) 4/6 inhibitors are a type of cell cycle regulation that prevents cell proliferation by blocking retinoblastoma protein (Rb) phosphorylation in the G1 to S phase transition. CDK 4/6 inhibitors are currently used mainly in patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer in combination with endocrine therapy. However, primary or acquired resistance to drugs severely affect drug efficacy. Our study aims at summarizing and visualizing the current research direction and development trend of CDK4/6 inhibitor resistance to provide clinicians and research power with a summary of the past and ideas for the future.MethodsThe Web of Science Core Collection and PubMed was searched for all included articles on CDK4/6 inhibitor resistance for bibliometric statistics and graph plotting. The metrological software and graphing tools used were R language version 4.2.0, Bibliometrix 4.0.0, Vosviewer 1.6.18, GraphPad Prism 9, and Microsoft Excel 2019.ResultsA total of 1278 English-language articles related to CDK4/6 inhibitor resistance were included in the Web of Science core dataset from 1996-2022, with an annual growth rate of14.56%. In PubMed, a total of 1123 articles were counted in the statistics, with an annual growth rate of 17.41% Cancer Research is the most included journal (102/1278, 7.98%) with an impact factor of 13.312 and is the Q1 of the Oncology category of the Journal Citation Reports. Professor Malorni Luca from Italy is probably the most contributing author in the current field (Publications 21/1278, 1.64%), while Prof. Turner Nicholas C from the USA is perhaps the most authoritative new author in the field of CDK4/6 inhibitor resistance (Total Citations2584, M-index 1.429). The main research efforts in this field are currently focused on Palbociclib and Abemaciclib. Studies on drug resistance mechanisms or post-drug resistance therapies focus on MEK inhibitors and related pathways, PI3K-AKT-MTOR pathways or inhibitors, EGFR-related pathways, EGFR inhibitors, TKI inhibitors, MAPK pathways and inhibitors, and so on.ConclusionThis study provides researchers with a reliable basis and guidance for finding authoritative references, understanding research trends, and mining research neglect directions.

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Arrested Developments: CDK4/6 Inhibitor Resistance and Alterations in the Tumor Immune Microenvironment.

Publications

Arrested Developments: CDK4/6 Inhibitor Resistance and Alterations in the Tumor Immune Microenvironment.

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