bims-cyhorp 2022-08-07 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2022‒08‒07
six papers selected by
Piotr Okupski

Severe acute radiation dermatitis after palbociclib therapy in the setting of palliative radiotherapy.
18F-FDG PET/CT Metabolic Response With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Treated With Cyclin-Dependent 4/6 Kinase Inhibitors.
Targeting CDK4 and 6 in Cancer Therapy: Emerging Preclinical Insights Related to Abemaciclib.
CDK4/6 inhibitors downregulate the ubiquitin-conjugating enzymes UBE2C/S/T involved in the ubiquitin-proteasome pathway in ER + breast cancer.
An open label, randomized phase 2 trial assessing the impact of food on the tolerability of abemaciclib in patients with advanced breast cancer.
Inhibiting Cyclin-Dependent Kinase 6 by Taurine: Implications in Anticancer Therapeutics.

J Oncol Pharm Pract. 2022 Aug 05. 10781552221118841

Severe acute radiation dermatitis after palbociclib therapy in the setting of palliative radiotherapy.

Kristine N Kim, Michael Salerno, Payal D Shah, Jennifer Matro, Michael J LaRiviere.

  INTRODUCTION: Cyclin-dependent-kinase 4/6(CDK4/6) inhibitors are widely used as a first-line systemic treatment for patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer. Although many patients with metastatic breast cancer require palliative radiotherapy (RT), there are limited data on the safety of combining a CDK4/6 inhibitor with palliative RT.CASE REPORT: Presented is a case of acute high-grade radiation dermatitis with low-dose palliative RT following administration of palbociclib. A 49-year-old woman with newly diagnosed hormone receptor-positive invasive ductal carcinoma of the left breast presented with lytic bone lesions in the left femur and lumbar spine. The patient initiated treatment with goserelin, tamoxifen, and palbociclib. She underwent prophylactic surgical fixation of the left femur and received post-operative RT encompassing the entire surgical nail (30 Gy/10 fractions) and palliative RT to the lumbar spine for pain relief (20 Gy/5 fractions). During cycle 4, palbociclib was stopped 3 days prior to the start of RT to reduce the risk of toxicity risk. However, 16 days after starting RT, she developed painful erythematous papules and bullae with moist desquamation on the left groin and lumbar spine.
MANAGEMENT & OUTCOME: Her symptoms were managed with topical Aquaphor-lidocaine, silver sulfadiazine, and aluminum acetate soaks. Dermatitis subsided to dry desquamation within 2 weeks. The patient denied late toxicity at 11 months follow-up.
DISCUSSION: Larger retrospective or prospective studies are needed to further elucidate the safety of combined CDK4/6 inhibitors and RT. In the meantime, special precautions are warranted in patients receiving combined therapy.

Keywords:  CDK4/6 inhibitor; Radiation dermatitis; metastatic breast cancer; palbociclib; radiotherapy

DOI:  https://doi.org/10.1177/10781552221118841
Clin Nucl Med. 2022 Sep 01. 47(9): e605-e606

18F-FDG PET/CT Metabolic Response With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Treated With Cyclin-Dependent 4/6 Kinase Inhibitors.

Nuh Filizoglu, Salih Ozguven, Tanju Yusuf Erdil.

ABSTRACT: Dysregulation of the cyclin D-CDK4/6-INK4-RB pathway, which leads to uncontrolled cell proliferation, is frequently observed in breast cancer. Recently, 3 CDK4/6 inhibitors have been FDA approved as first-line treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Despite promising clinical results, the metabolic response to treatment with these new drugs has not been elaborately demonstrated yet. Herein, we presented a patient with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer who demonstrated a complete metabolic response on 18F-FDG PET/CT to treatment with a CDK4/6 inhibitor (ribociclib).

DOI: https://doi.org/10.1097/RLU.0000000000004177
Oncologist. 2022 Aug 02. pii: oyac138. [Epub ahead of print]

Targeting CDK4 and 6 in Cancer Therapy: Emerging Preclinical Insights Related to Abemaciclib.

Seth A Wander, Neil O'Brien, Lacey M Litchfield, Declan O'Dea, Claudia Morato Guimaraes, Dennis J Slamon, Shom Goel.

  Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+) breast cancer (BC). In metastatic disease, strategies involving endocrine therapy combined with CDK4 and 6 inhibitors (CDK4 and 6i) improve clinical outcomes in HR+ BCs. CDK4 and 6i prevent retinoblastoma tumor suppressor protein phosphorylation, thereby blocking the transcription of E2F target genes, which in turn inhibits both mitogen and estrogen-mediated cell proliferation. In this review, we summarize preclinical data pertaining to the use of CDK4 and 6i in BC, with a particular focus on several of the unique chemical, pharmacologic, and mechanistic properties of abemaciclib. As research efforts elucidate the novel mechanisms underlying abemaciclib activity, potential new applications are being identified. For example, preclinical studies have demonstrated abemaciclib can exert antitumor activity against multiple tumor types and can cross the blood-brain barrier. Abemaciclib has also demonstrated distinct activity as a monotherapeutic in the treatment of BC. Accordingly, we also discuss how a greater understanding of mechanisms related to CDK4 and 6 blockade highlight abemaciclib's unique in-class properties, and could pave new avenues for enhancing its therapeutic efficacy.

Keywords:  CDK4 and 6; abemaciclib; antitumor; breast neoplasms; preclinical

DOI:  https://doi.org/10.1093/oncolo/oyac138
Clin Transl Oncol. 2022 Aug 02.

CDK4/6 inhibitors downregulate the ubiquitin-conjugating enzymes UBE2C/S/T involved in the ubiquitin-proteasome pathway in ER + breast cancer.

Chih-Yi Lin, Chung-Jen Yu, Chun-Yu Liu, Ta-Chung Chao, Chi-Cheng Huang, Ling-Ming Tseng, Jiun-I Lai.

  Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR( +)) (also known as luminal type) is the most prevalent category of breast cancer, comprising ~ 70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR( +) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteasome, and many others. The ubiquitin-proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins. By transcriptional profiling of the HR( +) breast cancer cell lines MCF7 and T47D treated with Palbociclib, we have uncovered a novel mechanism that demonstrates that the CDK4/6 inhibitors suppress the expression of three ubiquitin-conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR( +) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate that the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR( +) breast cancer cells demonstrate dependence on the UBE2C. Our study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer.

Keywords:  Breast cancer; CDK4/6 inhibitor; UBE2C, UBE2S, UBE2T

DOI:  https://doi.org/10.1007/s12094-022-02881-0
Breast Cancer Res Treat. 2022 Aug 01.

An open label, randomized phase 2 trial assessing the impact of food on the tolerability of abemaciclib in patients with advanced breast cancer.

Elgene Lim, Frances Boyle, Meena Okera, Sherene Loi, Sema Sezgin Goksu, Gertjan van Hal, Sonya C Chapman, Jonathon Colby Gable, Yanyun Chen, Gregory L Price, Anwar M Hossain, M Corona Gainford, Meritxell Bellet Ezquerra.

  PURPOSE: Abemaciclib, a CDK4 & 6 inhibitor, is indicated for advanced breast cancer treatment. Diarrhea is a frequently associated adverse event of abemaciclib. The study objective was to investigate if food intake impacts local gastrointestinal toxicity.METHODS: This Phase 2 study (I3Y-MC-JPCP, NCT03703466) randomized 72 patients 1:1:1 to receive abemaciclib 200 mg monotherapy twice daily (1) with a meal, (2) in a modified fasting state or (3) without regard to food. Primary endpoints included: incidence of investigator assessed severe (≥ Grade 3), prolonged (> 7 days) Grade 2 diarrhea, treatment discontinuation, dose modifications, and loperamide utilization during the first 3 cycles of treatment. Patient outcomes were captured via a daily electronic diary. Pharmacokinetics (PK) are reported.
RESULTS: Incidence of investigator assessed severe diarrhea (Grade ≥ 3) was 1.4% (1 patient in Arm 1). Median duration of Grade 3 diarrhea was 1 day by both investigator assessment (1 patient in Arm 1) and patient-reported assessment (1 patient each in Arms 1 and 3). Median duration of investigator-assessed Grade 2 diarrhea was 2 days overall. No patient discontinued treatment due to diarrhea. Nine patients (12.7%) had a dose reduction, and 7 patients (9.9%) had a dose omission due to diarrhea. Ninety-four percent of patients used loperamide at least once. Abemaciclib PK was comparable across the 3 arms.
CONCLUSION: The results suggest that diarrhea incidence associated with abemaciclib was unrelated to timing of food intake, was predominantly low grade, of short duration and well managed with loperamide and dose modifications.

Keywords:  Breast cancer; CDK4/6 inhibitor; Tolerability

DOI:  https://doi.org/10.1007/s10549-022-06690-5
ACS Omega. 2022 Jul 26. 7(29): 25844-25852

Inhibiting Cyclin-Dependent Kinase 6 by Taurine: Implications in Anticancer Therapeutics.

Mohd Yousuf, Anas Shamsi, Taj Mohammad, Naved Azum, Sulaiman Y M Alfaifi, Abdullah M Asiri, Abdelbaset Mohamed Elasbali, Asimul Islam, Md Imtaiyaz Hassan, Qazi Mohd Rizwanul Haque.

Cyclin-dependent kinase 6 (CDK6) is linked with a cyclin partner and plays a crucial role in the early stages of cancer development. It is currently a potential drug target for developing therapeutic molecules targeting cancer therapy. Here, we have identified taurine as an inhibitor of CDK6 using combined in silico and experimental studies. We performed various experiments to find the binding affinity of taurine with CDK6. Molecular docking analysis revealed critical residues of CDK6 that are involved in taurine binding. Fluorescence measurement studies showed that taurine binds to CDK6 with a significant binding affinity, with a binding constant of K = 0.7 × 107 M-1 for the CDK6-taurine complex. Enzyme inhibition assay suggested taurine as a good inhibitor of CDK6 possessing an IC50 value of 4.44 μM. Isothermal titration calorimetry analysis further confirmed a spontaneous binding of taurine with CDK6 and delineated the thermodynamic parameters for the CDK6-taurine system. Altogether, this study established taurine as a CDK6 inhibitor, providing a base for using taurine and its derivatives in CDK6-associated cancer and other diseases.

DOI: https://doi.org/10.1021/acsomega.2c03479