Abstract
BackgroundCombined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2− breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance.MethodsIn this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance.ResultsWe show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2− breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2− breast cancer models.ConclusionsThese data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2− breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.
Highlights
Combined targeting of CDK4/6 and ER is the standard of care for patients with advanced ER+/ HER2− breast cancer
Acquired resistance to CDK4/6 inhibitor monotherapy is associated with loss of dependence on pRb and activation of PI3K/mTOR signaling In order to assess the molecular alterations directly associated with the acquirement of resistance to CDK4/6 therapy, we developed in vitro and in vivo models of acquired resistance to palbociclib monotherapy
The EFM19 (ER+/HER2−; PIK3CA mt) breast cancer cell line was conditioned through long-term exposure to increasing concentrations of palbociclib until the cells continued to proliferate in the presence of drug at concentrations greater than the cellular IC50 (78 nmol/L) (Fig. 1a)
Summary
Combined targeting of CDK4/6 and ER is the standard of care for patients with advanced ER+/ HER2− breast cancer. Targeting CDK4/6 signaling in combination with endocrine therapies significantly improves progression-free survival (PFS) overall survival [1] in patients with advanced estrogen receptor-positive /HER2-negative (ER+/ HER2−) breast cancer [2,3,4] and is the standard of care for this disease. Preclinical work in our laboratory first demonstrated that hormone receptor-positive breast cancer cell lines are differentially sensitive to the CDK4/6 inhibitor palbociclib when compared to other breast cancer subgroups [5] Clinical translation of these data led to the subsequent approval of palbociclib for the treatment of advanced breast cancer in combination with hormonal targeted therapy [5, 6]. This in turn leads to cell cycle progression from G1 to S phase and subsequent cell proliferation [8]
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