ABSTRACT
Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R-induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER-independent PIK3CA-mutant breast cancer.
Subject(s)
Aniline Compounds/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis Regulatory Proteins/antagonists & inhibitors , Apoptosis/drug effects , BH3 Interacting Domain Death Agonist Protein/antagonists & inhibitors , Bcl-2-Like Protein 11/agonists , Estradiol , Estrogen Receptor alpha/physiology , Mammary Neoplasms, Experimental/drug therapy , Neoplasm Proteins/physiology , Neoplasms, Hormone-Dependent/drug therapy , Neuropeptides/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Sulfonamides/pharmacology , Thiazoles/pharmacology , Aniline Compounds/administration & dosage , Animals , Antineoplastic Agents, Hormonal/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bcl-2-Like Protein 11/biosynthesis , Bcl-2-Like Protein 11/genetics , Bcl-2-Like Protein 11/physiology , Cell Line, Tumor , Class I Phosphatidylinositol 3-Kinases , Cocarcinogenesis , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Drug Synergism , Estradiol/toxicity , Estrogen Receptor alpha/drug effects , Female , Fulvestrant/administration & dosage , Fulvestrant/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Gene Knock-In Techniques , Mammary Neoplasms, Experimental/chemically induced , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Nude , Mutation, Missense , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Neoplasms, Hormone-Dependent/chemically induced , Neoplasms, Hormone-Dependent/genetics , Neoplasms, Hormone-Dependent/pathology , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/physiology , Sulfonamides/administration & dosage , Thiazoles/administration & dosageABSTRACT
Metabolic changes induced by oncogenic drivers of cancer contribute to tumor growth and are attractive targets for cancer treatment. Here, we found that increased growth of PTEN-mutant cells was dependent on glutamine flux through the de novo pyrimidine synthesis pathway, which created sensitivity to the inhibition of dihydroorotate dehydrogenase, a rate-limiting enzyme for pyrimidine ring synthesis. S-phase PTEN-mutant cells showed increased numbers of replication forks, and inhibitors of dihydroorotate dehydrogenase led to chromosome breaks and cell death due to inadequate ATR activation and DNA damage at replication forks. Our findings indicate that enhanced glutamine flux generates vulnerability to dihydroorotate dehydrogenase inhibition, which then causes synthetic lethality in PTEN-deficient cells due to inherent defects in ATR activation. Inhibition of dihydroorotate dehydrogenase could thus be a promising therapy for patients with PTEN-mutant cancers.Significance: We have found a prospective targeted therapy for PTEN-deficient tumors, with efficacy in vitro and in vivo in tumors derived from different tissues. This is based upon the changes in glutamine metabolism, DNA replication, and DNA damage response which are consequences of inactivation of PTENCancer Discov; 7(4); 380-90. ©2017 AACR.See related article by Brown et al., p. 391This article is highlighted in the In This Issue feature, p. 339.
Subject(s)
Enzyme Inhibitors/administration & dosage , Neoplasms/metabolism , Oxidoreductases Acting on CH-CH Group Donors/genetics , PTEN Phosphohydrolase/genetics , Pyrimidines/biosynthesis , Animals , Ataxia Telangiectasia Mutated Proteins/genetics , DNA Damage/drug effects , DNA Replication/drug effects , Dihydroorotate Dehydrogenase , Fibroblasts/metabolism , Gene Knockout Techniques , Glutamine/metabolism , Humans , Metabolic Networks and Pathways/drug effects , Mice , Neoplasms/drug therapy , Neoplasms/genetics , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Oxidoreductases Acting on CH-CH Group Donors/metabolism , PTEN Phosphohydrolase/metabolismABSTRACT
Phosphatase and tensin homolog on chromosome ten (PTEN) is a tumor suppressor and an antagonist of the phosphoinositide-3 kinase (PI3K) pathway. We identified a 576-amino acid translational variant of PTEN, termed PTEN-Long, that arises from an alternative translation start site 519 base pairs upstream of the ATG initiation sequence, adding 173 N-terminal amino acids to the normal PTEN open reading frame. PTEN-Long is a membrane-permeable lipid phosphatase that is secreted from cells and can enter other cells. As an exogenous agent, PTEN-Long antagonized PI3K signaling and induced tumor cell death in vitro and in vivo. By providing a means to restore a functional tumor-suppressor protein to tumor cells, PTEN-Long may have therapeutic uses.
