bims-cyhorp 2021-09-19 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2021–09–19
ten papers selected by
Piotr Okupski,

Publisher Correction: Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer.
Management of hormone receptor-positive, human epidermal growth factor 2-negative metastatic breast cancer.
Metastatic hormone receptor-positive breast cancer in CDK 4/6 era: An outcome audit.
Neoadjuvant Therapy of Cyclin-Dependent Kinase 4/6 Inhibitors Combined with Endocrine Therapy in HR+/HER2- Breast Cancer: A Systematic Review and Meta-Analysis.
Development of pteridin-7(8H)-one analogues as highly potent cyclin-dependent kinase 4/6 inhibitors: Synthesis, structure-activity relationship, and biological activity.
Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients.
Combined CDK inhibition overcomes MEK inhibitor resistance in plexiform neurofibroma of neurofibromatosis type I.
Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor.
Cyclin D1b induces changes in the macrophage phenotype resulting in promotion of tumor metastasis.
A comprehensive nanopore sequencing methodology deciphers the complete transcriptional landscape of cyclin dependent kinase 4 (CDK4) in human malignancies.

Nat Commun. 2021 Sep 16. 12(1): 5588

Publisher Correction: Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer.

Carla L Alves, Sidse Ehmsen, Mikkel G Terp, Neil Portman, Martina Tuttolomondo, Odd L Gammelgaard, Monique F Hundebøl, Kamila Kaminska, Lene E Johansen, Martin Bak, Gabriella Honeth, Ana Bosch, Elgene Lim, Henrik J Ditzel.

DOI: https://doi.org/10.1038/s41467-021-25901-z
Breast Cancer Res Treat. 2021 Sep 13.

Management of hormone receptor-positive, human epidermal growth factor 2-negative metastatic breast cancer.

Jason A Mouabbi, C Kent Osborne, Rachel Schiff, Mothaffar F Rimawi.

  Estrogen receptor (ER) is the major driver of most metastatic breast cancers (mBCs). Endocrine therapy (ET) is the most effective treatment for ER + mBC, but its effectiveness is limited by high rates of de novo and acquired resistance. A growing understanding of the biological characteristics and complexity of the ER pathway and the mechanisms of ET resistance has led to the development of a new generation of targeted therapies. One such mechanism is the cell cycle signaling pathways, which lead to the development of cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) that have, in turn, transformed the management of such tumors. Another important mechanism is the alteration of the phosphatidylinositol 3'-kinase/AKT/mammalian target of rapamycin pathway. Drugs targeting each component of these pathways are currently used in clinical practice, and several more are in development. As a result, a myriad of new targeted therapies are consistently being added to the clinical oncologist armamentarium. Navigating the evolving and highly complex treatment landscape of HR + /HER2- mBC remains both an art and a challenge. In this review, we discuss the biological features of HR + /HER2- mBC and the different mechanisms of resistance to ET. We also discuss the management of mBC as the disease changes from endocrine-sensitive to endocrine-resistant.

Keywords:  AI; CDK4/6 inhibitor; ER+; Endocrine therapy; Estrogen receptor positive; HR+; Hormone receptor positive; Metastatic breast cancer; Review; SERD; SERM

DOI:  https://doi.org/10.1007/s10549-021-06383-5
J Cancer Res Ther. 2021 Jul-Sep;17(4):17(4): 994-997

Metastatic hormone receptor-positive breast cancer in CDK 4/6 era: An outcome audit.

Rajeev Krishnappa Lakkavalli, Jitendra Kumar Pehalajani, Venkatesh Tirumala, Govind K Babu, Dassappa Loknatha, Linu Abraham Jacob, Suresh M C Babu, A H Rudresha, Lokesh Nagendrappa Kadabur, Smitha C Saldanha, G V Giri.

   Background: The treatment landscape of metastatic hormone receptor (HR) positive breast cancer has been changed in recent years. Availability of CDK 4/6 inhibitor and other hormone therapy has changed the treatment algorithm for these patient, we retrospectively analyzed our metastatic HR positive breast cancer patients.
Materials and Methods: In this study, we retrospectively analyzed the case records of hr positive metastatic breast cancer patient treated at department of medical oncology from October 2016 to September 2018. Demographical characteristics, site of metastasis, objective response and clinical benefit response and toxicity profile were analyzed.
Results: We treated a total of 178 patients of MBC with HT at our center during the study period. One hundred fifty-two patients received HT alone (control group) and 26 patients received HT and CDK 4/6 inhibitor (study group). The median age of patients was 56 and 58 years in the control group and study group. The ORR was 41.7 versus 57.9 (95% CI [1.01-2.56]), and the CBR was 66.1% versus 78.9%; (CI [1.18-3.56]) (P < 0.05) of the patients in control and study groups, respectively.
Conclusions: Among patients with HR-positive, advanced breast cancer, hormone therapy is efficacious addition of CDK 4/6 inhibitor improve the efficacy with tolerable side effects.

Keywords:  CDK4/6 inhibitors; hormone receptor; metastatic breast cancer

DOI:  https://doi.org/10.4103/jcrt.JCRT_853_18
Oncol Res Treat. 2021 Aug 12. 1-11

Neoadjuvant Therapy of Cyclin-Dependent Kinase 4/6 Inhibitors Combined with Endocrine Therapy in HR+/HER2- Breast Cancer: A Systematic Review and Meta-Analysis.

Kai Hong, Lingli Yao, Xianneng Sheng, Dan Ye, Yu Guo.

   BACKGROUND: Cyclin-dependent kinase (CDK) 4/6 inhibitors have been advocated for adjuvant therapy of metastatic hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- breast cancer (BC). However, the efficiency of adding CDK 4/6 inhibitors to neoadjuvant therapy was not unequivocal.
OBJECTIVE: The aim of the study was to evaluate the efficiency and toxicity of neoadjuvant CDK 4/6 inhibitors + endocrine therapy (ET) versus neoadjuvant endocrine monotherapy or standard neoadjuvant chemotherapy in HR+/HER2- BC.
METHOD: We searched PubMed, the Cochrane Library, Web of Science, and Embase online databases for randomized controlled trials and single-arm studies written in English until April 2021.
RESULTS: Five studies comparing CDK 4/6 inhibitors + ET as neoadjuvant treatments to ET alone and 2 studies comparing neoadjuvant CDK 4/6 inhibitors + ET to neoadjuvant chemotherapy were analysed. Neoadjuvant CDK 4/6 inhibitors + ET improved the rate of complete cell cycle arrest (CCCA: central Ki67 < 2.7%, odds ratio [OR] = 7.91, 95% confidence interval [CI] = 4.81-13.03, p < 0.001), increased the risk of adverse events (AEs; especially ≥3 AEs; AEs of all grades: OR = 9.10, 95% CI = 2.39-34.58, p = 0.001; AEs ≥3: OR = 12.24, 95% CI = 4.17-35.88, p < 0.001), led to no significant differences in pathological complete response (pCR) in patients with BC (OR = 0.34, 95% CI = 0.04-2.85, p = 0.318) compared to endocrine monotherapy. Moreover, subgroup analysis showed that the 3 types of CDK 4/6 inhibitors all improved the rate of CCCA (ribociclib: OR = 10.31, 95% CI = 3.59-29.61, p < 0.001; palbociclib: OR = 7.39, 95% CI = 1.26-43.40, p = 0.027, and abemaciclib: OR = 8.28, 95% CI = 3.41-20.11, p < 0.001). Compared to neoadjuvant chemotherapy, neoadjuvant CDK 4/6 inhibitors plus ET decreased the risk of AEs ≥3 (OR = 0.50, 95% CI = 0.29-0.87, p = 0.015) and showed similar ability to reach pCR (OR = 0.50, 95% CI = 0.12-2.07, p = 0.342) and reduce the residual cancer burden (RCB, RCB 0-1: OR = 0.47, 95% CI = 0.18-1.22, p = 0.121; RCB 2-3: OR = 2.30, 95% CI = 0.89-5.91, p = 0.084).
CONCLUSIONS: The results suggested that combination therapy had increased efficacy and toxicity compared to endocrine monotherapy and showed similar efficacy to and better safety than neoadjuvant chemotherapy.

Keywords:  Cyclin-dependent kinase 4/6 inhibitors; Endocrine therapy; Hormone receptor+/epidermal growth factor receptor 2− breast cancer; Neoadjuvant chemotherapy; Neoadjuvant treatment

DOI:  https://doi.org/10.1159/000518573
Bioorg Chem. 2021 Sep 02. pii: S0045-2068(21)00701-X. [Epub ahead of print]116 105324

Development of pteridin-7(8H)-one analogues as highly potent cyclin-dependent kinase 4/6 inhibitors: Synthesis, structure-activity relationship, and biological activity.

Qiu Li, Lin Chen, Yu-Feng Ma, Xie-Er Jian, Jia-Hao Ji, Wen-Wei You, Pei-Liang Zhao.

  CDK4/6 have been validated as the cancer therapeutic targets. Here, we describe a series of pteridin-7(8H)-one analogues as potent CDK4/6 inhibitors. Among them, the most promising compound 7s demonstrated remarkable and broad-spectrum antiproliferative activities toward HCT116, HeLa, MDA-MB-231, and HT-29 cells with IC50 values of 0.65, 0.70, 0.39, and 2.53 μM, respectively, which were more potent than that of the anticancer drug Palbociclib. Interestingly, 7s also manifested the greatest inhibitory activities toward both CDK4/cyclin D3 and CDK6/cyclin D3 (IC50 = 34.0 and 65.1 nM, respectively), which was comparable with Palbociclib. Additionally, molecular simulation indicated that 7s bound efficiently at the ATPbindingsitesofCDK4 and CDK6. Further mechanistic studies revealed that compound 7s could concentration-dependently induce cell cycle arrest and apoptosis in HeLa cells. Takentogether, 7s represents a promising novel CDK4/6 inhibitor for the potential treatment of cancer.

Keywords:  Antiproliferative activity; CDK4/6 inhibitor; Pteridin-7(8H)-one

DOI:  https://doi.org/10.1016/j.bioorg.2021.105324
ESMO Open. 2021 Sep 09. pii: S2059-7029(21)00192-7. [Epub ahead of print]6(5): 100231

Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients.

M Del Re, C Omarini, L Diodati, M Palleschi, I Meattini, S Crucitta, G Lorenzini, C Isca, A Fontana, L Livi, F Piacentini, S Fogli, U De Giorgi, R Danesi.

   BACKGROUND: Proton-pump-inhibitors (PPIs) are frequently prescribed for the management of anticancer drug-related gastrointestinal symptoms. Palbociclib is a weak base with pH-dependent solubility and potential drug-drug interaction at the absorption level may affect clinical pharmacokinetics. The current study was aimed at investigating the effect of co-administration of PPIs and palbociclib on progression-free survival (PFS) in metastatic breast cancer (mBC) patients.
PATIENTS AND METHODS: Patients affected by estrogen receptor-positive, human epidermal growth factor receptor 2-negative mBC, who were candidates for first-line treatment with palbociclib, were enrolled in this retrospective observational study. Patients were defined as 'no concomitant PPIs' if no PPIs were administered during palbociclib treatment, and as 'concomitant PPIs' if the administration of PPIs covered the entire or not less than two-thirds of treatment with palbociclib. All clinical interventions were made according to clinical practice.
RESULTS: A total of 112 patients were enrolled in the study; 56 belonged to the 'no concomitant PPIs' group and 56 to the 'concomitant PPIs' group. Seventy-one patients were endocrine-sensitive and received palbociclib and letrozole, and 43 were endocrine-resistant and were treated with palbociclib and fulvestrant. The most prescribed PPI was lansoprazole. Patients taking PPIs had a shorter PFS than those taking palbociclib and endocrine therapy alone (14.0 versus 37.9 months, P < 0.0001). Multivariate analysis confirmed concomitant PPIs as the only independent predictive factor for shorter PFS (P = 0.0002). PFS was significantly longer in estrogen-sensitive mBC with no concomitant PPIs compared with patients taking PPIs or estrogen-resistant patients, with and without PPIs (P < 0.0001). No correlation with adverse events was found when considering grade >2 hematological toxicities [Common Terminology Criteria for Adverse Events (CTCAE) scale].
CONCLUSIONS: The present study demonstrates that concomitant use of PPIs in mBC patients treated with palbociclib has a detrimental effect on PFS. Therefore, it is recommended to prescribe PPIs with caution in these patients, strictly adhering to the indications in the summary of product characteristics (RCP).

Keywords:  PFS; breast cancer; drug-drug interactions; palbociclib; proton pump inhibitors

DOI:  https://doi.org/10.1016/j.esmoop.2021.100231
J Invest Dermatol. 2021 Sep 14. pii: S0022-202X(21)01672-9. [Epub ahead of print]

Combined CDK inhibition overcomes MEK inhibitor resistance in plexiform neurofibroma of neurofibromatosis type I.

Wei Wang, Xi-Wei Cui, Yi-Hui Gu, Cheng-Jiang Wei, Yue-Hua Li, Jie-Yi Ren, Man-Hon Chung, Re-Han-Gu-Li Aimaier, Hai-Bing Zhang, Qing-Feng Li, Zhi-Chao Wang.

  MEK1/2 inhibitors (MEKi) have recently achieved surprising success in treating unresectable plexiform neurofibromas (PNFs). However, few studies have investigated the mechanisms of MEKi resistance in PNF patients. We determined the efficacy of 6 different MEKi for treating PNFs, explored drug resistance mechanisms and identified potential combination therapies to overcome resistance. By screening drug efficacy among 6 MEKi in human NF1-deficient PNF cell lines, TAK-733 was found reduce PNF cell viability the most. We then cultured the TAK-733 resistant cells and explored potential targets for further treatment. Both high-throughput drug screening and RNA sequencing analyses of MEKi-resistant PNF cells identified cyclin-dependent kinase inhibitors (CDKi) as potential agents for PNFs. Dinaciclib, a CDKi, showed synergistic effects on MEKi-resistant cells. Coadministration of dinaciclib and TAK-733 significantly reduced cell viability, inhibited sphere formation and colony formation. Dinaciclib did not affect MEK signaling but decreased the expression of several prosurvival proteins, including survivin and CDK1, to induce apoptosis and inhibit mitosis. TAK-733/dinaciclib combination therapy induced tumor reduction in PNF patient-derived xenografts mouse models. Therefore, the combination of MEKi and CDKi may be promising for treating inoperable PNFs, especially when drug resistance exists. Our findings provide evidence for future clinical trials with MEKi-resistant PNF patients.

Keywords:  MEK inhibitor; dinaciclib; drug resistance; neurofibromatosis type I; plexiform neurofibroma

DOI:  https://doi.org/10.1016/j.jid.2021.07.164
Cancer Cell. 2021 Sep 11. pii: S1535-6108(21)00449-9. [Epub ahead of print]

Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor.

Kevin Freeman-Cook, Robert L Hoffman, Nichol Miller, Jonathan Almaden, John Chionis, Qin Zhang, Koleen Eisele, Chaoting Liu, Cathy Zhang, Nanni Huser, Lisa Nguyen, Cinthia Costa-Jones, Sherry Niessen, Jordan Carelli, John Lapek, Scott L Weinrich, Ping Wei, Elizabeth McMillan, Elizabeth Wilson, Tim S Wang, Michele McTigue, Rose Ann Ferre, You-Ai He, Sacha Ninkovic, Douglas Behenna, Khanh T Tran, Scott Sutton, Asako Nagata, Martha A Ornelas, Susan E Kephart, Luke R Zehnder, Brion Murray, Meirong Xu, James E Solowiej, Ravi Visswanathan, Britton Boras, David Looper, Nathan Lee, Jadwiga R Bienkowska, Zhou Zhu, Zhengyan Kan, Ding Ying, Xinmeng Jasmine Mu, Cecilia Oderup, Shahram Salek-Ardakani, Michael A White, Todd VanArsdale, Stephen G Dann.

  The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.

Keywords:  CCNE1; CDK2; CDK4; CDK6; MYC; cell cycle; hormone-receptor-positive breast cancer; innate immune response; palbociclib; therapy resistance

DOI:  https://doi.org/10.1016/j.ccell.2021.08.009
Exp Biol Med (Maywood). 2021 Sep 13. 15353702211038511

Cyclin D1b induces changes in the macrophage phenotype resulting in promotion of tumor metastasis.

Yuxue Wang, Yi Liu, Lei Xiang, Lintao Han, Xiaowei Yao, Yibing Hu, Fenghua Wu.

  In breast cancer, tumor-associated macrophages with activated phenotypes promote tumor invasion and metastasis. The more aggressive mesenchymal-like breast cancer cells have a selective advantage, skewing macrophages toward the more immunosuppressive subtype. However, the mechanism underlying this shift is poorly understood. Cyclin D1b is a highly oncogenic variant of cyclin D1. Our previous study showed that non-metastatic epithelial-like breast cancer cells were highly metastatic in vivo when cyclin D1b was overexpressed. The present study determined whether cyclin D1b contributed to the interaction between breast cancer cells and macrophages. The results showed that cyclin D1b promoted the invasion of breast cancer cells in vitro. Specifically, through overexpression of cyclin D1b, breast cancer cells regulated the differentiation of macrophages into a more immunosuppressive M2 phenotype. Notably, tumor cells overexpressing cyclin D1b activated macrophages and induced migration of breast cancer cells. Further investigations indicated that SDF-1 mediated macrophage activation through breast cancer cells overexpressing cyclin D1b. These results revealed a previously unknown link between aggressive breast cancer cells and Tumor-associated macrophages, and highlighted the importance of cyclin D1b activity in the breast cancer microenvironment.

Keywords:  Cyclin D1b; SDF-1; breast cancer; tumor invasion; tumor metastasis; tumor-associated macrophage

DOI:  https://doi.org/10.1177/15353702211038511
FEBS J. 2021 Sep 17.

A comprehensive nanopore sequencing methodology deciphers the complete transcriptional landscape of cyclin dependent kinase 4 (CDK4) in human malignancies.

Panagiotis G Adamopoulos, Konstantina Athanasopoulou, Panagiotis Tsiakanikas, Andreas Scorilas.

  CDK4 is a member of the cyclin-dependent kinases, a family of protein kinases with outstanding roles in signalling pathways, transcription regulation and cell division. Defective or overactivated CDK4/cyclin D1 pathway leads to enhanced cellular proliferation, thus being implicated in human cancers. Although the biological role of CDK4 has been extensively studied, its pre-mRNA processing mechanism under normal or pathological conditions is neglected. Thus, the identification of novel CDK4 mRNA transcripts, especially protein-coding ones, could lead to the identification of new diagnostic and/or prognostic biomarkers or new therapeutic targets. In the present study, instead of using the "gold-standard" direct RNA sequencing application, we designed and employed a targeted nanopore sequencing approach, which offers higher sequencing depth and enables the thorough investigation of new mRNAs of any target gene. Our study elucidates for the first time the complex transcriptional landscape of the human CDK4 gene, highlighting the existence of previously unknown CDK4 transcripts with new alternative splicing events and protein-coding capacities. The relative expression levels of each novel CDK4 transcript in human malignancies were elucidated with custom qPCR-based assays. The presented wide spectrum of CDK4 transcripts (CDK4 v.2 - v.42) is only the first step to distinguish and assemble the missing pieces regarding the exact functions and implications of this fundamental kinase in cellular homeostasis and pathophysiology.

Keywords:  CDK4; alternative splicing; cyclin-dependent kinases; long-read sequencing; nanopore sequencing

DOI:  https://doi.org/10.1111/febs.16201