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CDk4/6 and Breast

Gary K Scott, David Chu, Ravneet Kaur, Julia Malato, Daniel E Rothschild, Katya Frazier, Serenella Eppenberger-Castori, Byron Hann, Ben Ho Park, Christopher C Benz
ERα phosphorylation at hinge site S294 (pS294) was recently shown to be essential for ER-dependent gene transcription and mediated by an unknown cyclin-dependent kinase (CDK). This study was undertaken to identify the exact CDK pathway mediating pS294 formation, and to determine if this phosphorylation event occurs with, and can be targeted to treat, the ligand-independent growth of breast cancers expressing endocrine-refractory ESR1 mutations. Using a newly developed anti-pS294 monoclonal antibody, a combination of CDK specific siRNA knockdown studies and a broad panel of CDK selective inhibitors against ligand (E2)-stimulated MCF7 cells, we first identified CDK2 as the primary mediator of pS294 formation and showed that CDK2-selective inhibitors like Dinaciclib, but not CDK4/6 inhibitors like Palbociclib, can selectively prevent pS294 formation and repress ER-dependent gene expression...
October 18, 2016: Oncotarget
C Yang, Z Li, T Bhatt, M Dickler, D Giri, M Scaltriti, J Baselga, N Rosen, S Chandarlapaty
Dysregulated activation of the CDK4/6 kinases is a hallmark of most mammary-derived carcinomas. ATP-competitive inhibitors against this complex have been recently advanced in the clinic and have shown significant activity, particularly against tumors driven by the estrogen receptor (ER). However, resistance to these compounds has begun to emerge often months to years after their initiation. We investigated potential mechanisms of resistance using cell line models that are highly sensitive to this class of drugs...
October 17, 2016: Oncogene
Dimitrios Zardavas, Konstantinos Tryfonidis, Theodora Goulioti, Martine Piccart
INTRODUCTION: The potential of molecular targeted therapy to improve the clinical outcomes of patients with early-stage breast cancer (BC) as adjuvant therapy has been first demonstrated through endocrine treatment. The introduction of HER2 blockade, through the successful clinical development of trastuzumab, changed the natural history of HER2-positive BC subtype. AREAS COVERED: There are ongoing efforts to augment further the use of targeted agents as adjuvant treatment in BC, hoping that early introduction of targeted therapy blocking key oncogenic drivers of micro-residual disease, will significantly improve clinical outcomes...
October 14, 2016: Expert Review of Anticancer Therapy
Cornelia Liedtke, Hans-Christian Kolberg
Systemic therapy of metastatic breast cancer may include chemotherapy, endocrine therapy, and targeted therapies (e.g., antibody-based approaches). These agents may be employed alone or in combination based on the patient's breast cancer subtype. Therefore, characterization of the disease phenotype is necessary and may include biopsy of the metastatic site. Novel therapeutic approaches include immunologic therapies, PARP inhibitors, PI3K inhibitors, and CDK4/6 inhibitors, which are currently under investigation in clinical trials...
August 2016: Breast Care
Gabriel N Hortobagyi, Salomon M Stemmer, Howard A Burris, Yoon-Sim Yap, Gabe S Sonke, Shani Paluch-Shimon, Mario Campone, Kimberly L Blackwell, Fabrice André, Eric P Winer, Wolfgang Janni, Sunil Verma, Pierfranco Conte, Carlos L Arteaga, David A Cameron, Katarina Petrakova, Lowell L Hart, Cristian Villanueva, Arlene Chan, Erik Jakobsen, Arnd Nusch, Olga Burdaeva, Eva-Maria Grischke, Emilio Alba, Erik Wist, Norbert Marschner, Anne M Favret, Denise Yardley, Thomas Bachelot, Ling-Ming Tseng, Sibel Blau, Fengjuan Xuan, Farida Souami, Michelle Miller, Caroline Germa, Samit Hirawat, Joyce O'Shaughnessy
Background The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). Methods In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease...
October 7, 2016: New England Journal of Medicine
(no author information available yet)
No abstract text is available yet for this article.
October 1, 2016: Cancer Research
Luca Malorni, Silvano Piazza, Yari Ciani, Cristina Guarducci, Martina Bonechi, Chiara Biagioni, Christopher D Hart, Roberto Verardo, Angelo Di Leo, Ilenia Migliaccio
Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib...
September 13, 2016: Oncotarget
Erik S Knudsen, Agnieszka K Witkiewicz
ER positive (ER+) and HER2 negative (HER2-) breast cancers are routinely treated based on estrogen dependence. CDK4/6 inhibitors in combination with endocrine therapy have significantly improved the progression-free survival of patients with ER+/HER2- metastatic breast cancer. Gene expression profiling in ER+/HER2- models was used to define the basis for the efficacy of CDK4/6 inhibitors and develop a gene expression signature of CDK4/6 inhibition. CDK4/6 inhibition robustly suppressed cell cycle progression of ER+/HER2- models and complements the activity of limiting estrogen...
August 18, 2016: Oncotarget
Rekha Gyanchandani, Karthik J Kota, Amruth R Jonnalagadda, Tanya Minteer, Beth A Knapick, Steffi Oesterreich, Adam M Brufsky, Adrian V Lee, Shannon L Puhalla
ESR1 mutations are frequently acquired in hormone-resistant metastatic breast cancer (MBC). CDK4/6 inhibition along with endocrine therapy is a promising strategy in hormone receptor-positive MBC. However, the incidence and impact of ESR1 mutations on clinical outcome in patients treated with CDK4/6 inhibitors have not been defined. In this study, we evaluated the frequency of ESR1 mutations in cfDNA from 16 patients with MBC undergoing palbociclib and letrozole therapy. Four common ESR1 mutations (D538G, Y537C, Y537N, and Y537S) were analyzed in serial blood draws using ddPCR...
August 19, 2016: Oncotarget
Marcus Schmidt
Endocrine therapy is the cornerstone in the treatment of hormone receptor-positive breast cancer. During the last decades, much has been learned about the subtle regulation of the cell cycle. In this tightly regulated network, cyclin-dependent kinases (CDKs) play a pivotal role. Especially CDK4/6 is the key regulator of the G1-S transition. Realizing its importance, specific inhibitors of CDK4/6 were developed. The drug most advanced in clinical development in this class is palbociclib (PD 0332991). This review highlights preclinical data and brings into focus early clinical trials that led to an accelerated approval by the US Food and Drug Administration (FDA) as first-line treatment in combination with letrozole in advanced hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer...
June 2016: Breast Care
Johannes Ettl
Palbociclib is the first inhibitor of the cyclin-dependent kinases (CDK) 4 and 6 to be introduced into clinical practice. Preclinical investigations led to its clinical development in advanced hormone receptor (HR)-positive breast cancer. To date, 2 significant clinical trials have been fully published. In this article, the results of these trials and their clinical relevance for the management of HR-positive advanced breast cancer are discussed.
June 2016: Breast Care
Romualdo Barroso-Sousa, Geoffrey I Shapiro, Sara M Tolaney
Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development...
June 2016: Breast Care
Jessica L F Teh, Timothy J Purwin, Evan J Greenawalt, Inna Chervoneva, Allison Goldberg, Michael A Davies, Andrew E Aplin
Aberrant cell-cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinases 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma. CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib, was recently FDA approved for the treatment of estrogen receptor-positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF promote CDK4/6 activation, suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit in combination with BRAF inhibitors and/or MEK inhibitors that are FDA-approved...
September 15, 2016: Cancer Research
Brendon Ladd, Anne Marie Mazzola, Teeru Bihani, Zhongwu Lai, James Bradford, Michael Collins, Evan Barry, Anne U Goeppert, Hazel M Weir, Kelly Hearne, Jonathan G Renshaw, Morvarid Mohseni, Elaine Hurt, Sanjoo Jalla, Haifeng Bao, Robert Hollingsworth, Corinne Reimer, Michael Zinda, Stephen Fawell, Celina M D'Cruz
Although endocrine therapy is successfully used to treat patients with estrogen receptor (ER) positive breast cancer, a substantial proportion of this population will relapse. Several mechanisms of acquired resistance have been described including activation of the mTOR pathway, increased activity of CDK4 and activating mutations in ER. Using a patient derived xenograft model harboring a common activating ER ligand binding domain mutation (D538G), we evaluated several combinatorial strategies using the selective estrogen receptor degrader (SERD) fulvestrant in combination with chromatin modifying agents, and CDK4/6 and mTOR inhibitors...
July 26, 2016: Oncotarget
Simon Peter Gampenrieder, Gabriel Rinnerthaler, Richard Greil
Endocrine therapy represents the basis for the treatment of estrogen receptor-positive breast cancer, but several tumors harbor intrinsic resistance and acquired resistance to endocrine therapy is inevitable in metastatic disease. Combination strategies of endocrine therapy with targeted agents are aimed to overcome endocrine resistance. The selective CDK4/6 inhibitor palbociclib has shown promising results in metastatic luminal breast cancer when used in combination with endocrine therapy both in the first-line setting as in pretreated women...
2016: Memo
Joline S J Lim, Nicholas C Turner, Timothy A Yap
Patnaik and colleagues report on the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of abemaciclib for the treatment of advanced solid cancers, demonstrating antitumor activity in advanced breast cancers as well as glioblastoma, melanoma, non-small cell lung cancer, colorectal cancer, and ovarian cancer. The development of abemaciclib and other CDK4/6 inhibitors should now be fully optimized through the use of novel predictive biomarkers of response and rational combinations. Cancer Discov; 6(7); 697-9...
July 2016: Cancer Discovery
(no author information available yet)
According to results from a phase II study, abemaciclib shows single-agent activity in women with metastatic HER2-negative, ER-positive breast cancer whose disease has progressed on endocrine therapy and chemotherapy. The objective response rate to this investigational CDK4/6 inhibitor was 19.7%, with 28.2% of responses lasting at least a year.
August 2016: Cancer Discovery
G Curigliano, P Gómez Pardo, F Meric-Bernstam, P Conte, M P Lolkema, J T Beck, A Bardia, M Martínez García, F Penault-Llorca, S Dhuria, Z Tang, N Solovieff, M Miller, E Di Tomaso, S A Hurvitz
OBJECTIVES: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting. MATERIALS AND METHODS: Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2...
August 2016: Breast: Official Journal of the European Society of Mastology
Ciara C O'Sullivan
INTRODUCTION: Breast cancer remains a major cause of morbidity and mortality worldwide. Given the central role of cyclin-dependent kinases in regulating cell division, there has been a longstanding interest in developing compounds which target the cyclin D1: CDK4/6 axis in breast cancer. The recent discovery of potent and selective CDK4/6 inhibitors (CDK4/6i) was an important breakthrough. AREAS COVERED: There are three CDK4/6i in clinical development (palbociclib, ribociclib and abemaciclib)...
August 2016: Expert Opinion on Pharmacotherapy
Adriana Priscila Trapé, Shuying Liu, Andrea Carolina Cortes, Naoto T Ueno, Ana Maria Gonzalez-Angulo
Among patients with hormone receptor (HR)-positive breast cancer, those with residual disease after neoadjuvant chemotherapy have a higher risk of relapse and poorer survival than those with a complete response. Previous studies have revealed a correlation between activation of cell cycle-regulating pathways in HR-positive breast cancer, particularly cyclin-dependent kinase (CDK) 4 and 6/cyclin D1 signaling, and resistance to standard therapies. Although CDK4/6 inhibition by palbociclib in combination with endocrine therapy has shown potent antiproliferative effects in HR-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, the potential role of palbociclib in re-sensitizing chemotherapy-resistant HR-positive breast cancer is not well defined...
2016: Journal of Cancer
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