bims-cyhorp 2022-05-01 papers

Issue of 2022–05–01
five papers selected by
Piotr Okupski,

RSC Adv. 2021 Sep 01. 11(47): 29227-29246

CDK4/6 inhibitors: a brief overview and prospective research directions.

Tenzin Adon, Dhivya Shanmugarajan, Honnavalli Yogish Kumar.

The discovery of cyclin-dependent kinases (CDK) and their mechanism in regulating the cell cycle process was considered a game-changer in cancer therapy. Cell cycle arrest and apoptosis were both triggered by their inhibition. The CDK4/6 complex acts as a checkpoint during the cell cycle transition from cell growth (G1) to DNA synthesis (S) phase and its deregulation or overexpression induces abnormal cell proliferation and cancer development. Consequently, targeting CDK4/6 has been proposed as a paradigm shift in the anticancer approach. The design and development of effective CDK4/6 inhibitors are increasingly becoming a promising cancer therapy evident with approved drugs such as palbociclib, ribociclib, and abemaciclib, etc. In this article, we explore the biological importance of CDK4/6 in cancer therapy, the development of resistance to monotherapy, and a short overview of PROTAC (Proteolysis Targeting Chimera), a unique and pioneering technique for degrading CDK4/6 enzymes. Overall, our prime focus is to discuss novel CDK4/6 inhibitors with diverse chemical classes and their correlation with computational studies.

DOI: https://doi.org/10.1039/d1ra03820f

Cancer Med. 2022 Apr 25.

Treatment patterns, effectiveness, and patient-reported outcomes of palbociclib therapy in Chinese patients with advanced breast cancer: A multicenter ambispective real-world study.

BACKGROUND: Palbociclib was the only available cyclin-dependent kinase 4/6 inhibitor in China until very recently, and its effect has not been systemically evaluated among Chinese patients. This study aims to assess the efficacy, safety and patient-reported outcomes (PROs) of palbociclib plus endocrine therapy (ET) in real-world China.
METHODS: An ambispective cohort study was conducted on patients with advanced HR+HER2- breast cancer who received palbociclib between July 2018, and November 2020 and were enrolled from 12 hospitals. Treatment patterns, survival outcomes, and safety events were documented, and PROs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items [EORTC QLQ-C30] and EuroQoL 5 dimensions [EQ-5D]) were analyzed. The Kaplan-Meier method was used to visualize and estimate the median progression-free survival (mPFS). Log-rank tests, Cox regressions, t tests, and chi-square tests were performed for comparison.
RESULTS: A total of 190 patients (median follow-up of 18.0 months) were enrolled. Palbociclib was mostly combined with aromatase inhibitors (66.3%), fulvestrant (32.6%), and tamoxifen (1.1%). The mPFS values were 21.0, 14.0, and 7.0 months with palbociclib administered in first- (n = 83), second- (n = 41) and subsequent-line settings (n = 66), respectively. Endocrine sensitivity was significantly associated with patient prognosis (mPFS: 23.0, 12.0, and 6.0 months for endocrine naïve, acquired, and primary resistant patients, respectively, p < 0.01). The outcome was worse for patients who failed to meet the inclusion criteria of PALOMA-3 than for those who met the criteria (later-line: 6.0 months vs. 9.0 months). The most common adverse events (AEs) were neutropenia (74.2%; grade 3/4: 30.0%), fatigue (48.4%), anemia (32.6%), and thrombocytopenia (22.1%). PRO data suggested that palbociclib plus ET significantly improved cognitive and emotional function, pain symptoms, and overall quality of life.
CONCLUSIONS: Palbociclib is effective for front-line use and for treating endocrine-sensitive patients in real-world China and is generally well tolerated. The prevalence of AEs in the Chinese population is different from that reported in the PALOMA-2/3 trials.

Keywords: adverse events; endocrine therapy; metastatic breast cancer; palbociclib; patient-reported outcomes; real-world study

DOI: https://doi.org/10.1002/cam4.4767

EBioMedicine. 2022 Apr 24. pii: S2352-3964(22)00194-3. [Epub ahead of print]79 104010

Immune effects of CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer: Relief from immunosuppression is associated with clinical response.

Fabio Scirocchi, Simone Scagnoli, Andrea Botticelli, Alessandra Di Filippo, Chiara Napoletano, Ilaria Grazia Zizzari, Lidia Strigari, Silverio Tomao, Enrico Cortesi, Aurelia Rughetti, Paolo Marchetti, Marianna Nuti.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are innovative small target molecules that, in combination with endocrine therapy, have recently been employed in the treatment of patients with HR+/HER2- metastatic breast cancer (mBC). In this prospective study, we investigate the impact of CDK4/6i on the immune profile of patients with HR+/HER2- mBC.
METHODS: Immune cell subsets were analysed using flow cytometry of peripheral blood mononuclear cells (PBMCs) isolated from patients with HR+/HER2- mBC, both before and during treatment. Regulatory T cells (Tregs) were identified using the markers CD4, CD25, CTLA4, CD45RA, and intracellular FOXP3. Monocytic and polymorphonuclear myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs) and other immune populations were analysed using CD45, CD14, CD66b, CD11c, HLA-DR, CD3, CD8, CD28, CD137, PD1, CD45RA, CCR7, and Ki67.
FINDINGS: The percentage of circulating Tregs and M/PMN-MDSCs was significantly downregulated from baseline during CDK4/6i-treatment (p<0.0001 and p<0.05, respectively). In particular, the effector Treg subset (CD4+CD25+FOXP3highCD45RA-) was strongly reduced (p<0.0001). The decrease in Treg levels was significantly greater in responder patients than in non-responder patients. Conversely, CDK4/6i treatment was associated with increased levels of CD4+ T cells and anti-tumour CD137+CD8+ T cells (p<0.05).
INTERPRETATION: CDK4/6i treatment results in downregulation of Tregs, M-MDSCs, and PMN-MDSCs, thus weakening tumour immunosuppression. This decrease is associated with response to treatment, highlighting the importance of unleashing immunity in cancer treatment efficacy. These results suggest a novel mechanism of immunomodulation in mBC and provide valuable information for the future design of novel treatments combining CDK4/6i with immunotherapy in other cancer settings.
FUNDING: Sapienza University of Rome.

Keywords: CDK4/6i; HR(+)/HER2(-) metastatic breast cancer; Immune modulation; MDSCs; Regulatory T cells; Treg

DOI: https://doi.org/10.1016/j.ebiom.2022.104010

Front Pharmacol. 2022 ;13 853993

LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer.

Jiahao Qiu, Xinfa Bai, Wenjing Zhang, Mingxu Ma, Wenyan Wang, Ye Liang, Hongbo Wang, Jingwei Tian, Pengfei Yu.

Triple negative breast cancer (TNBC) is a subtype of breast cancer with significant malignancy and poor prognosis but effective treatments are limited. Given the critical role of CDK4/6 in cell cycle and the apparent success of CDK4/6 inhibitors against certain cancer, this study attempted to utilize hydrophobic tagging technology to develop a CDK4/6 degrader against TNBC. We based on the chemical structure of the major metabolite of a clinically approved CDK4/6 inhibitor, abemaciclib, to synthesize three compounds and evaluated their in vitro cytotoxicity. LPM3770277 stood out as the most promising compound which was further confirmed by a series of binding and CDK4/6 degradation studies. LPM3770277 was able to bind to CDK4/6, and time-dependently and dose-dependently increased CDK4/6 protein degradation. Mechanistic study revealed that LPM3770277 exerted its CDK4/6 degradation effect via two machineries: proteasome and lysosome-promoted autophagy. Using in vivo TNBC xenograft cancer model, we found that LPM3770277 demonstrated superior anti-tumor efficacy and safety as compared to abemaciclib, although both compounds exerted similar effects on cell cycle arrest. In conclusion, this study for the first time developed and characterized a CDK4/6 degrader against TNBC using hydrophobic tags, which strongly suggests the viability of hydrophobic tags as a strategy to develop potential treatments against TNBC.

Keywords: CDK4/6 degrader; hydrophobic tagging; lysosome-promoted autophagy; proteasome; triple-negative breast cancer

DOI: https://doi.org/10.3389/fphar.2022.853993

J Med Chem. 2022 Apr 29.

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy.

Zhenfeng Shi, Lei Tian, Taotao Qiang, Jingyi Li, Yue Xing, Xiaodong Ren, Chang Liu, Chengyuan Liang.

Herein, we discuss more than 50 cyclin-dependent kinase (CDK) inhibitors that have been approved or have undergone clinical trials and their therapeutic application in multiple cancers. This review discusses the design strategies, structure-activity relationships, and efficacy performances of these selective or nonselective CDK inhibitors. The theoretical basis of early broad-spectrum CDK inhibitors is similar to the scope of chemotherapy, but because their toxicity is greater than the benefit, there is no clinical therapeutic window. The notion that selective CDK inhibitors have a safer therapeutic potential than pan-CDK inhibitors has been widely recognized during the research process. Four CDK4/6 inhibitors have been approved for the treatment of breast cancer or for prophylactic administration during chemotherapy to protect bone marrow and immune system function. Furthermore, the emerging strategies in the field of CDK inhibitors are summarized briefly, and CDKs continue to be widely pursued as emerging anticancer drug targets for drug discovery.

DOI: https://doi.org/10.1021/acs.jmedchem.1c02064