Oncotarget

Priority Research Papers:

Effective combination therapies in preclinical endocrine resistant breast cancer models harboring ER mutations

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 and Celina M. D’Cruz _

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Oncotarget. 2016; 7:54120-54136. https://doi.org/10.18632/oncotarget.10852

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Abstract

Brendon Ladd1, Anne Marie Mazzola1, Teeru Bihani1, Zhongwu Lai1, James Bradford2, Michael Collins1, Evan Barry1, Anne U. Goeppert2, Hazel M. Weir2, Kelly Hearne2, Jonathan G. Renshaw2, Morvarid Mohseni1, Elaine Hurt3, Sanjoo Jalla3, Haifeng Bao3, Robert Hollingsworth3, Corinne Reimer1, Michael Zinda1, Stephen Fawell1 and Celina M. D’Cruz1

1 Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA

2 Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, UK

3 Oncology, Medimmune, Gaithersburg, MD, USA

Correspondence to:

Celina M. D’Cruz, email:

Keywords: advanced metastatic breast cancer, ER mutations, endocrine resistance, combination therapy

Received: October 09, 2015 Accepted: July 06, 2016 Published: July 26, 2016

Abstract

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. In this model, fulvestrant binds WT and MT ER, reduces ER protein levels, and downregulated ER target gene expression. Addition of JQ1 or vorinostat to fulvestrant resulted in tumor regression (41% and 22% regression, respectively) though no efficacy was seen when either agent was given alone. Interestingly, although the CDK4/6 inhibitor palbociclib and mTOR inhibitor everolimus were efficacious as monotherapies, long-term delayed tumor growth was only observed when co-administered with fulvestrant. This observation was consistent with a greater inhibition of compensatory signaling when palbociclib and everolimus were co-dosed with fulvestrant. The addition of fulvestrant to JQ1, vorinostat, everolimus and palbociclib also significantly reduced lung metastatic burden as compared to monotherapy. The combination potential of fulvestrant with palbociclib or everolimus were confirmed in an MCF7 CRISPR model harboring the Y537S ER activating mutation. Taken together, these data suggest that fulvestrant may have an important role in the treatment of ER positive breast cancer with acquired ER mutations.


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