2458 Despite dramatic improvements in treatment over the past 40 years, acute lymphoblastic leukemia (ALL) remains one of the most common causes of death from disease in childhood. Glucocorticoids are among the most effective agents used in the treatment of lymphoid malignancies, and patient response to treatment is an important determinant of long-term outcome in childhood ALL. In spite of its clinical significance, the molecular basis of glucocorticoid resistance is still poorly understood. The aim of this study was to develop an experimental model system to define clinically relevant mechanisms of glucocorticoid resistance in childhood ALL. An in vivo model of childhood ALL has been developed in our laboratory, using patient biopsies established as xenografts in immune-deficient nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice. This model is highly representative of the human disease (Lock et al., Blood, 99: 4100-4108, 2002). The in vivo responses of these xenografts to the glucocorticoid dexamethasone (DEX) correlated significantly with patient outcome (p 1 μM) in xenografts from six patients, five of whom died of their disease. In contrast, four DEX-sensitive xenografts (IC50 values 2-fold in sensitive xenografts within 8 hours of treatment. In contrast, Bim induction was dramatically attenuated in DEX-resistant xenografts. These results have identified a clinically significant and novel mechanism of glucocorticoid resistance in childhood ALL, which occurs downstream of receptor-ligand interactions, but upstream of the signalling pathway resulting in Bim induction and apoptosis.

Novel mechanisms of glucocorticoid resistance in childhood acute lymphoblastic leukemia.

Targeting cell-cycle machinery in cancer

Deregulation of the cyclin D-CDK4/6-INK4-RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle-specific mechanisms and cell cycle-nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.32020

Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review

Targeting CDK2 in cancer: challenges and opportunities for therapy

Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.

Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.

Introduction and Objective: HER2 amplification is found in approximately 20% of patients with breast cancer and is associated with poor prognosis. Trastuzumab, a humanized anit-HER2 antibody, has been shown to improve patient outcomes, but clinical efficacy for this treatment is limited by the high rate of drug resistance. Cyclin E overexpression and cyclin-dependent kinase 2 (CDK2) activation correlate with trastuzumab resistance, and the underlying mechanisms of this correlation are an area of active study. In this work, we examined the contribution of cyclin E/CDK2-mediated Smad3 noncanonical phosphorylation to trastuzumab resistance in HER2+ breast cancer. Methods : Trastuzumab resistant BT474R2 cells were developed by culturing BT474 cells in trastuzumab-supplemented media for 18 months. These cells were then inoculated into immunodeficient mice and treated with trastuzumab twice weekly. BT474 and BT474R2 cells were used to study cell proliferation, phosphorylation in the Smad3 linker region and transcription factor activities with a living cell array. Results : Inhibition of cyclin E activity with CDK2 inhibitor therapy (CDK2i, 600 nM) significantly decreased BT474R2 cell proliferation. CDK2i treatment led to decreased phosphorylation at T179 (p Conclusions: Taken together, overexpression of cyclin E leads to Smad3 noncanonical phosphorylation and results in trastuzumab resistance in HER2+ breast cancer. CDK2i treatment may be a promising therapeutic strategy for patients with trastuzumab resistance. Citation Format: Decker JT, Wan L, Shea LD, Jeruss JS. Cyclin E affects Smad3 pathway in trastuzumab resistant HER2+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-03-16.

Abstract P4-03-16: Cyclin E affects Smad3 pathway in trastuzumab resistant HER2+ breast cancer

// Shreyas S. Rao 1 , Jenna Stoehr 2 , Danijela Dokic 3 , Lei Wan 4 , Joseph T. Decker 5 , Kristine Konopka 6 , Alexandra L. Thomas 7 , Jia Wu 8 , Virginia G. Kaklamani 9 , Lonnie D. Shea 3, 5 and Jacqueline S. Jeruss 3, 4, 5, 6 1 Department of Chemical and Biological Engineering, University of Alabama, Tuscaloosa, AL, USA 2 Weinberg College of Arts and Sciences, Northwestern University, Evanston, IL, USA 3 Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL, USA 4 Department of Surgery, University of Michigan, Ann Arbor, MI, USA 5 Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA 6 Department of Pathology, University of Michigan, Ann Arbor, MI, USA 7 Driskill Graduate Program, Northwestern University, Chicago, IL, USA 8 Department of Chemical and Biological Engineering, McCormick School of Engineering and Applied Science, Northwestern University, Evanston, IL, USA 9 Breast Oncology Program, CTRC, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Correspondence to: Jacqueline S. Jeruss, email: jjeruss@med.umich.edu Keywords: CDK2, eribulin, TGFβ, Smad3, triple negative breast cancer Received: March 31, 2017     Accepted: July 12, 2017     Published: August 10, 2017 ABSTRACT Activation of CDK2 in triple negative breast cancer (TNBC) can contribute to non-canonical phosphorylation of a TGFβ signaling component, Smad3, promoting cell proliferation and migration. Inhibition of CDK2 was shown to decrease breast cancer oncogenesis. Eribulin chemotherapy was used effectively in the treatment of TNBC. To this end, we tested therapeutic efficacy of a novel CDK2/9 inhibitor, CYC065, eribulin, and the combination of CYC065 and eribulin in 3 different TNBC cell lines, and an in vivo xenograft model. Specifically, we characterized cell proliferation, apoptosis, migration, cell cycle associated protein expression, treatment-related transcription factor activity, and tumor growth in TNBC. Treatment with CYC065 and eribulin in combination had a superior effect on decreasing cell proliferation, inducing apoptosis, and inhibiting migration in TNBC cell lines in vitro . Combination therapy inhibited non-canonical Smad3 phosphorylation at the T179 site in the protein linker region, and resulted in increased p15 and decreased c-myc expression. In a transcription factor array, combination treatment significantly increased activity of AP1 and decreased activity of factors including NFκB, SP1, E2F, and SMAD3. In an in vivo xenograft model of TNBC, individual and combination treatments resulted in a decrease in both tumor volume and mitotic indices. Taken together, these studies highlight the potential of this novel drug combination, CYC065 and eribulin, to suppress the growth of TNBC cells in vitro and in vivo, warranting further clinical investigation.

Synergistic effect of eribulin and CDK inhibition for the treatment of triple negative breast cancer

The efficacy of trastuzumab, a treatment for HER2+ breast cancer, can be limited by the development of resistance. Cyclin E (CCNE) overexpression has been implicated in trastuzumab resistance. We s...

Cyclin E overexpression confers resistance to trastuzumab through noncanonical phosphorylation of SMAD3 in HER2+ breast cancer.

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Abstract P4-03-16: Cyclin E affects Smad3 pathway in trastuzumab resistant HER2+ breast cancer

Synergistic effect of eribulin and CDK inhibition for the treatment of triple negative breast cancer

Cyclin E overexpression confers resistance to trastuzumab through noncanonical phosphorylation of SMAD3 in HER2+ breast cancer.