ABSTRACT
BACKGROUND: Combined 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. METHODS: In 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. RESULTS: We 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. CONCLUSIONS: These 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.
Subject(s)
Breast Neoplasms/drug therapy , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Drug Resistance, Neoplasm , Estrogen Receptor alpha/antagonists & inhibitors , Phosphatidylinositol 3-Kinases/chemistry , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Drug Evaluation, Preclinical , Female , Humans , Mice, Nude , Molecular Targeted Therapy , Phosphatidylinositol 3-Kinases/metabolism , Pregnancy , Protein Kinase Inhibitors/pharmacology , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Smac mimetic compounds targeting the inhibitor of apoptosis proteins (IAP) baculoviral IAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression. We explored this tenet in an unbiased manner by searching for small interfering RNAs that are able to confer resistance to the Smac mimetic compound LBW242. Among the screening hits were multiple components of the tumor necrosis factor alpha (TNFalpha) signaling pathway as well as X-linked inhibitor of apoptosis (XIAP) itself. Here, we show that in a subset of highly sensitive tumor cell lines, activity of LBW242 is dependent on TNFalpha signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNFalpha induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNFalpha-mediated apoptosis.
Subject(s)
Inhibitor of Apoptosis Proteins/physiology , Intracellular Signaling Peptides and Proteins/physiology , Mitochondrial Proteins/physiology , RNA, Small Interfering/genetics , Tumor Necrosis Factor-alpha/physiology , X-Linked Inhibitor of Apoptosis Protein/physiology , Apoptosis/drug effects , Apoptosis/physiology , Apoptosis Regulatory Proteins , Cell Death , Cell Line, Tumor , Conserved Sequence , Female , Humans , Oligopeptides/pharmacology , Ovarian Neoplasms , RNA Interference/physiology , RNA, Neoplasm/genetics , Signal Transduction , X-Linked Inhibitor of Apoptosis Protein/geneticsABSTRACT
PURPOSE OF REVIEW: Recently, RNA interference has evolved into a powerful research tool to functionally characterize genes. Genome-wide RNA interference reagents can study the loss-of-function phenotypes of candidate genes in the context of various disease model systems. In this review, we discuss the data from the most recent studies using RNA interference reagents with a focus on RNA interference-based genomic screening as a tool to expand our knowledge about the molecular basis of cancer. RECENT FINDINGS: Tumorigenesis is the result of the progressive accumulation of mutations in genes controlling cell proliferation and death. Various genes carrying these alterations are known to be directly linked to tumor growth; however, how to translate this knowledge into effective chemotherapeutics, nontoxic to normal cells, is still a subject of intensive research. SUMMARY: Loss-of-function studies offer a potential for validation of known and unrecognized tumor-associated targets. RNA interference-mediated gene knockdown can be exploited to study the reprogrammed circuitry of genes, discover gene interactions restricted to cancer cells and identify mechanisms of chemoresistance in cancer cells. In addition, the simultaneous use of cancer drugs and RNA interference also provides a paradigm to develop strategies to inactivate essential genes promoting neoplastic growth.
