bims-cyhorp 2022-03-13 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2022–03–13
ten papers selected by
Piotr Okupski,

The emerging CDK4/6 inhibitor for breast cancer treatment.
Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer.
Cyclin-dependent Kinases 4/6 Inhibitors in Neuroendocrine Neoplasms: from Bench to Bedside.
Biological Effects of Cyclin-Dependent Kinase Inhibitors Ribociclib, Palbociclib and Abemaciclib on Breast Cancer Bone Microenvironment.
Defining the mechanisms underlying cyclin dependent kinase control of HIF-1α.
Drug-Induced Eosinophilic Pneumonia as an Adverse Event of Abemaciclib.
Modulation of the estrogen/erbB2 receptors crosstalk by CDK4/6 inhibition triggers sustained senescence in estrogen receptor and erbB2 positive breast cancer.
A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer.
Cyclin-dependent kinases in DNA damage response.
Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer.

Mol Cell Pharmacol. 2021 ;13(3): 9-12

The emerging CDK4/6 inhibitor for breast cancer treatment.

M Saeed Sheikh, Siem A Satti.

The cyclin-dependent kinase (CDK) inhibitors have emerged as important cancer therapeutics. To date, three CDK4/6 inhibitors in combination with endocrine therapy have been approved by the U.S. Food and Drug Administration for the treatment of hormone receptor-positive, HER2-negative advanced breast cancer. These include, palbociclib, ribociclib and abemaciclib. More recently, a newer CDK4/6 inhibitor named dalpiciclib has been tested in the phase III DAWNA-1 study, which is a randomized, double-blind, placebo-controlled trial that investigates dalpiciclib in combination with fulvestrant in hormone receptor-positive, HER2-negative advanced breast cancer patients that have relapsed or progressed on prior endocrine therapy. Dalpiciclib is an oral agent and an emerging ATP-competitive CDK4/6 inhibitor. The interim results of DAWNA-1 study revealed that dalpiciclib in combination with fulvestrant significantly prolonged the progression-free survival. The clinical use and side effects of palbociclib, ribociclib and abemaciclib as well as dalpiciclib are reviewed here.

Keywords: Abemaciclib; Breast cancer; Dalpiciclib; Fulvestrant; Palbociclib; Ribociclib
Breast Cancer Res. 2022 Mar 05. 24(1): 17

Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer.

April C Watt, Shom Goel.

  Pharmacological inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are now an established standard of care for patients with advanced hormone receptor-positive breast cancer. The canonical mechanism underlying CDK4/6 inhibitor activity is the suppression of phosphorylation of the retinoblastoma tumor suppressor protein, which serves to prevent cancer cell proliferation. Recent data suggest that these agents induce other diverse effects within both tumor and stromal compartments, which serve to explain aspects of their clinical activity. Here, we review these phenomena and discuss how they might be leveraged in the development of novel CDK4/6 inhibitor-containing combination treatments. We also briefly review the various known mechanisms of acquired resistance in the clinical setting.

Keywords:  Breast cancer; CDK4/6; Cell cycle; Combination therapy; Cyclin-dependent kinase; Drug resistance

DOI:  https://doi.org/10.1186/s13058-022-01510-6
Curr Oncol Rep. 2022 Mar 09.

Cyclin-dependent Kinases 4/6 Inhibitors in Neuroendocrine Neoplasms: from Bench to Bedside.

Maria João de Sousa, Lorenzo Gervaso, Monica Isabel Meneses-Medina, Francesca Spada, Omar Abdel-Rahman, Nicola Fazio.

   PURPOSE OF REVIEW: Cyclin-dependent kinases (CDKs) are key regulators that play an important role in cell division. Palbociclib, ribociclib and abemaciclib showed significant antitumor activity in several malignancies and, recently, also a myeloprotective effect for trilaciclib when added to chemotherapy. The purpose of this review is to highlight the current evidence for CDK4/6 inhibitors in neuroendocrine neoplasms (NENs).
RECENT FINDINGS: Preclinical results showed a promising antitumor activity of CDK4/6 inhibitors in neuroendocrine tumors (NETs), but so far, the very few small clinical trials did not show a strong impact on progression free survival (PFS) and objective response in NETs. Meanwhile, the CDK4/6 inhibitor trilaciclib revealed significant effects in reducing chemotherapy-induced myelosuppression in small cell lung cancer (SCLC). Up to date, CDK4/6 inhibitors are still considered investigational in NETs as antitumor agents, whereas trilaciclib can be used in the routine clinical practice in extensive stage SCLC patients for reducing myelotoxicity of standard chemotherapy.

Keywords:  Abemaciclib; trilaciclib; Neuroendocrine tumors; CDK4/6 inhibitors; Palbociclib; Ribociclib

DOI:  https://doi.org/10.1007/s11912-022-01251-x
Int J Mol Sci. 2022 Feb 24. pii: 2477. [Epub ahead of print]23(5):

Biological Effects of Cyclin-Dependent Kinase Inhibitors Ribociclib, Palbociclib and Abemaciclib on Breast Cancer Bone Microenvironment.

Michele Iuliani, Sonia Simonetti, Giulia Ribelli, Andrea Napolitano, Umile Giuseppe Longo, Bruno Vincenzi, Paolo Orsaria, Vincenzo Denaro, Giuseppe Tonini, Daniele Santini, Pantano Francesco.

  The CDK4/6 inhibitors (CDKi) palbociclib, ribociclib, and abemaciclib are currently approved in combination with anti-estrogen therapy for the treatment of advanced and/or metastatic hormone receptor-positive/HER2-neu-negative breast cancer patients. Given the high incidence of bone metastases in this population, we investigated and compared the potential effects of palbociclib, ribociclib, and abemaciclib on the breast cancer bone microenvironment. Primary osteoclasts (OCs) and osteoblasts (OBs) were obtained from human monocyte and mesenchymal stem cells, respectively. OC function was evaluated by tartrate-resistant acid phosphatase assay and real-time PCR; OB activity was assessed by an alizarin red assay. OB/breast cancer co-culture models were generated via the seeding of MCF-7 cells on a layer of OBs, and tumor cell proliferation was analyzed using flow cytometry. Here, we showed that ribociclib, palbociclib, and abemaciclib exerted similar inhibitory effects on the OC differentiation and expression of bone resorption markers without affecting OC viability. On the other hand, the three CDKi did not affect the ability of OB to produce bone matrix, even if the higher doses of palbociclib and abemaciclib reduced the OB viability. In OB/MCF-7 co-culture models, palbociclib demonstrated a lower anti-tumor effect than ribociclib and abemaciclib. Overall, our results revealed the direct effects of CDKi on the tumor bone microenvironment, highlighting differences potentially relevant for clinical practice.

Keywords:  CDK4/6 inhibitors; bone tumor microenvironment; breast cancer; osteoblasts; osteoclasts

DOI:  https://doi.org/10.3390/ijms23052477
Oncotarget. 2022 ;13 454-455

Defining the mechanisms underlying cyclin dependent kinase control of HIF-1α.

Noel A Warfel.



Keywords:  HIF-1; SMURF2; cyclin dependent kinase; hypoxia

DOI:  https://doi.org/10.18632/oncotarget.28208
Cureus. 2022 Jan;14(1): e21741

Drug-Induced Eosinophilic Pneumonia as an Adverse Event of Abemaciclib.

Yuki Mitarai, Yukari Tsubata, Miki Hyakudomi, Takeshi Isobe.

  In 2020, a 45-year-old woman was started on fulvestrant and abemaciclib therapy to treat breast cancer which had recurred in her left breast after surgery. We were able to control her cancer using this treatment; however, the ground-glass opacity in the lower lobe of her right lung expanded, along with an increase in her peripheral blood eosinophil count. She was referred to the respiratory medicine department for a detailed examination including bronchoscopy. We discovered a high proportion of eosinophils in her bronchoalveolar lavage fluid and diagnosed the condition as drug-induced eosinophilic pneumonia. The ground-glass change improved after steroid administration. In this case, the adverse effects of abemaciclib, a cyclin-dependent kinase 4/6 inhibitor playing an essential role in breast cancer treatment, were discovered by combining blood, imaging, and bronchoalveolar lavage fluid findings. This contributed to an early introduction of treatment and prevented the deterioration of her quality of life.

Keywords:  abemaciclib; breast cancer; drug-induced lung injury; eosinophil; eosinophilic pneumonia

DOI:  https://doi.org/10.7759/cureus.21741
Clin Cancer Res. 2022 Mar 07. pii: clincanres.3185.2021. [Epub ahead of print]

Modulation of the estrogen/erbB2 receptors crosstalk by CDK4/6 inhibition triggers sustained senescence in estrogen receptor and erbB2 positive breast cancer.

Lucia Viganò, Alberta Locatelli, Adele Ulisse, Barbara Galbardi, Matteo Dugo, Diego Tosi, Carlo Tacchetti, Tiziana Daniele, Balázs Győrffy, Lorenzo Sica, Marina Macchini, Milvia Zambetti, Stefania Zambelli, Giampaolo Bianchini, Luca Gianni.

PURPOSE: The interplay between estrogen-receptor (ER) and erb-B tyrosine-kinase receptors (RTKs) impacts growth and progression of ER+/HER2+ breast cancer (BC) and generates mitogenic signals converging onto the Cyclin-D1/CDK4/6 complex. We probed this crosstalk combining endocrine-therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab) and CDK4/6-inhibition (palbociclib) (PFHPert).
METHODS: Cytotoxic drug effects, interactions and pharmacodynamics were studied after 72 hours of treatment and over 6 more days of culture after drug wash-out in three ER+/HER2+, two HER2low, and two ER-/HER2+ BC cell lines. We assessed gene-expression dynamic and association with Ki67 downregulation in 28 patients with ER+/HER2+ BC treated with neoadjuvant PFHPert in NA-PHER2 Trial (NCT02530424).
RESULTS: In vitro, palbociclib and/or fulvestrant induced a functional activation of RTKs signalling. PFHPert had additive or synergistic antiproliferative activity, interfered with resistance mechanisms linked to the RTKs/Akt/MTORC1 axis and induced sustained senescence. Unexpected synergism was found in HER2low cells. In patients, Ki67 downregulation at week2 and surgery were significantly associated to upregulation of senescence-related genes (p=7.7E-4 and p=1.8E-4, respectively). Activation of MTORC1 pathway was associated with high Ki67 at surgery (p = 0.019).
CONCLUSIONS: Resistance associated with the combination of drugs targeting ER and HER2 can be bypassed by co-targeting Rb, enhancing transition from quiescence to sustained senescence. MTORC1 pathway activation is a potential mechanism of escape and RTKs functional activation may be an alternative pathway for survival also in ER+/HER2low tumor. PFHPert combination is an effective chemotherapy-free regimen for ER+/HER2+ BC and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for further treatment refinement.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-3185
Int J Mol Sci. 2022 Mar 07. pii: 2892. [Epub ahead of print]23(5):

A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer.

Chenchen Tian, Yufan Wei, Jianjun Li, Zhi Huang, Qiong Wang, Yingxue Lin, Xingping Lv, Yanan Chen, Yan Fan, Peiqing Sun, Rong Xiang, Antao Chang, Shuang Yang.

  In recent years, three PARP inhibitors and three CDK4/6 inhibitors have been approved by the FDA for the treatment of recurrent ovarian cancer and advanced ER-positive breast cancer, respectively. However, the clinical benefits of the PARPi or CDK4/6i monotherapy are not as satisfied as expected and benefit only a fraction of patients. Current studies have shown therapeutic synergy for combinations of PARPi and CDK4/6i in breast and ovarian cancers with homologous recombination (HR) proficiency, which represents a new synthetic lethal strategy for treatment of these cancers regardless HR status. Thus, any compounds or strategies that can combine PARP and CDK4/6 inhibition will likely have great potential in improving clinic outcomes and in benefiting more patients. In this study, we developed a novel compound, ZC-22, that effectively inhibited both PARP and CDK4/6. This dual-targeting compound significantly inhibited breast and ovarian cancer cells by inducing cell cycle arrest and severe DNA damage both in vitro and in vivo. Interestingly, the efficacy of ZC-22 is even higher than the combination of PARPi Olaparib and CDK4/6i Abemaciclib in most breast and ovarian cancer cells, suggesting that it may be an effective alternative for the PARPi and CDK4/6i combination therapy. Moreover, ZC-22 sensitized breast and ovarian cancer cells to cisplatin treatment, a widely used chemotherapeutic agent. Altogether, our study has demonstrated the potency of a novel CDK4/6 and PARP dual inhibitor, which can potentially be developed into a monotherapy or combinatorial therapy with cisplatin for breast and ovarian cancer patients with HR proficiency.

Keywords:  CDK4/6 inhibitor; PARP inhibitor; ZC-22; breast cancer; ovarian cancer

DOI:  https://doi.org/10.3390/ijms23052892
Biochim Biophys Acta Rev Cancer. 2022 Mar 07. pii: S0304-419X(22)00041-5. [Epub ahead of print] 188716

Cyclin-dependent kinases in DNA damage response.

Mateusz Kciuk, Adrianna Gielecińska, Somdutt Mujwar, Mariusz Mojzych, Renata Kontek.

  The cyclin-dependent kinase (CDK) family plays a critical role in a variety of signaling pathways that regulate transcription and cell-cycle progression. Recently, the role of CDKs in DNA damage response (DDR) has emerged. CDKs affect both damage signaling and DNA repair, contributing to the fidelity of the cell division process as well as the maintenance of genomic integrity following DNA damage. This is due to the modulatory role of CDKs on double-strand break repair (DSBR) components, including their influence on enzymes involved in homologous recombination (HR) and non-homologous end-joining (NHEJ). In this review, the impact of CDKs on DDR and DNA repair is discussed.

Keywords:  Cell-cycle checkpoint; Cyclin-dependent kinase (CDK); DNA damage response (DDR); DNA repair

DOI:  https://doi.org/10.1016/j.bbcan.2022.188716
N Engl J Med. 2022 03 10. 386(10): 942-950

Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer.

Gabriel N Hortobagyi, Salomon M Stemmer, Howard A Burris, Yoon-Sim Yap, Gabe S Sonke, Lowell Hart, Mario Campone, Katarina Petrakova, Eric P Winer, Wolfgang Janni, Pierfranco Conte, David A Cameron, Fabrice André, Carlos L Arteaga, Juan P Zarate, Arunava Chakravartty, Tetiana Taran, Fabienne Le Gac, Paolo Serra, Joyce O'Shaughnessy.

BACKGROUND: In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known.
METHODS: Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings.
RESULTS: After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval [CI], 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P = 0.008). No new safety signals were observed.
CONCLUSIONS: First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. (Funded by Novartis; MONALEESA-2 ClinicalTrials.gov number, NCT01958021.).

DOI: https://doi.org/10.1056/NEJMoa2114663