Functional Characterization of an Isoform-Selective Inhibitor of PI3K-p110β as a Potential Anticancer Agent

Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02115, USA.
Cancer Discovery (Impact Factor: 19.45). 05/2012; 2(5):425-33. DOI: 10.1158/2159-8290.CD-12-0003
Source: PubMed

ABSTRACT Genetic approaches have shown that the p110β isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110β-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collection of compounds possessing activities against kinases in the PI3K superfamily and identified a potent and selective p110β inhibitor: KIN-193. We show that KIN-193 is efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110β activation or PTEN loss. Broad profiling across a panel of 422 human tumor cell lines shows that the PTEN mutation status of cancer cells strongly correlates with their response to KIN-193. Together, our data provide the first pharmacologic evidence that PTEN-deficient tumors are dependent on p110β in animals and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110β while sparing other PI3K isoforms. SIGNIFICANCE: We report the first functional characterization of a p110β-selective inhibitor, KIN-193, that is efficacious as an antitumor agent in mice. We show that this class of inhibitor holds great promise as a pharmacologic agent that could be used to address the potential therapeutic benefit of treating p110β-dependent PTEN-deficient human tumors.

Download full-text


Available from: Nathanael Gray, Aug 21, 2015
  • Source
    • "At least theoretically, distinct PI3K Class I requirements could influence the efficiency of preconditioning treatments in subsets of patients at risk for myocardial infarction and presenting with medication and co-morbidities that differentially affect Class IA and IB PI3K [28] [29] [30]. Likewise, selective PI3K isoform inhibitors used in the treatment of inflammatory diseases and cancer [31] [32] [33] may affect the efficacy of preconditioning treatments in the heart of these patients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute myocardial infarction, the clinical manifestation of ischemia-reperfusion (IR) injury, is a leading cause of death worldwide. Like ischemic preconditioning (IPC) induced by brief episodes of ischemia and reperfusion, ouabain preconditioning (OPC) mediated by Na/K-ATPase signaling protects the heart against IR injury. Class I PI3K activation is required for IPC, but its role in OPC has not been investigated. While PI3K-IB is critical to IPC, studies have suggested that ouabain signaling is PI3K-IA-specific. Hence, a pharmacological approach was used to test the hypothesis that OPC and IPC rely on distinct PI3K-I isoforms. In Langendorff-perfused mouse hearts, OPC was initiated by 4min of ouabain 10μM and IPC was triggered by 4cycles of 5min ischemia and reperfusion prior to 40min of global ischemia and 30min of reperfusion. Without affecting PI3K-IB, ouabain doubled PI3K-IA activity and Akt phosphorylation at Ser(473). IPC and OPC significantly preserved cardiac contractile function and tissue viability as evidenced by left ventricular developed pressure and end-diastolic pressure recovery, reduced lactate dehydrogenase release, and decreased infarct size. OPC protection was blunted by the PI3K-IA inhibitor PI-103, but not by the PI3K-IB inhibitor AS-604850. In contrast, IPC-mediated protection was not affected by PI-103 but was blocked by AS-604850, suggesting that PI3K-IA activation is required for OPC while PI3K-IB activation is needed for IPC. Mechanistically, PI3K-IA activity is required for ouabain-induced Akt activation but not PKCε translocation. However, in contrast to PKCε translocation which is critical to protection, Akt activity was not required for OPC. Further studies shall reveal the identity of the downstream targets of this new PI3K IA-dependent branch of OPC. These findings may be of clinical relevance in patients at risk for myocardial infarction with underlying diseases and/or medication that could differentially affect the integrity of cardiac PI3K-IA and IB pathways. Copyright © 2014. Published by Elsevier Ltd.
    Journal of Molecular and Cellular Cardiology 01/2015; 80. DOI:10.1016/j.yjmcc.2014.12.021 · 5.22 Impact Factor
  • Source
    • "We speculate that this p110b-depend- ent rebound of PIP 3 requires several hours to manifest for two main reasons: (1) the time required for maximal BYL719-depen- dent release of the negative feedbacks leading to tyrosine phosphorylation of PI3K activators (e.g., ERBB3) and subsequent p110b recruitment, and (2) since p110b is a relatively inefficient enzyme in comparison to p110a (Beeton et al., 2000), PIP 3 accumulation can only be observed after sufficient time following activation. Although p110b has been identified as the primary PI3K isoform driving PI3K signaling in PTEN null tumors (Jia et al., 2008; Ni et al., 2012), the experiments in this study suggest that p110b activation also promotes the viability of p110a-driven breast cancers following treatment with p110a-s- pecific inhibitors. In vivo, p110a inhibition blocked tumor growth but did not induce tumor shrinkage in either the HER2-amplified or PIK3CA mutant xenograft models. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BYL719, which selectively inhibits the alpha isoform of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110a), is currently in clinical trials for the treatment of solid tumors, especially luminal breast cancers with PIK3CA mutations and/or HER2 amplification. This study reveals that, even among these sensitive cancers, the initial efficacy of p110α inhibition is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110β isoform. Importantly, the reactivation of PI3K mediated by p110β does not invariably restore AKT phosphorylation, demonstrating the limitations of using phospho-AKT as a surrogate to measure PI3K activation. Consistently, we show that the addition of the p110β inhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-amplified and PIK3CA mutant cancers. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer Cell 12/2014; 27(1). DOI:10.1016/j.ccell.2014.11.007 · 23.89 Impact Factor
  • Source
    • "The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in many human cancers, often via molecular abnormalities such as PIK3CA mutations or loss of phosphatase and tensin homolog (PTEN) function (Engelman, 2009; Hollander et al., 2011; Samuels et al., 2004). Preclinical models and early clinical data in several tumor types suggested that PIK3CA mutations and loss of PTEN function can result in increased sensitivity to therapies targeting the PI3K/AKT/mTOR signaling pathway (Di Nicolantonio et al., 2010; Engelman et al., 2008; Ihle et al., 2009; Janku et al., 2011b; Moroney et al., 2011; Ni et al., 2012; Tsimberidou et al., 2012; Wee et al., 2008; Weigelt et al., 2011). Patients with gynecological and breast tumors and PIK3CA mutations demonstrated a partial response (PR) rate of 30% in early-phase clinical trials with PI3K/AKT/mTOR inhibitors compared to 10% in patients without PIK3CA mutations (Janku et al., 2012b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite a wealth of preclinical studies, it is unclear whether PIK3CA or phosphatase and tensin homolog (PTEN) gene aberrations are actionable in the clinical setting. Of 1,656 patients with advanced, refractory cancers tested for PIK3CA or PTEN abnormalities, PIK3CA mutations were found in 9% (146/1,589), and PTEN loss and/or mutation was found in 13% (149/1,157). In multicovariable analysis, treatment with a phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitor was the only independent factor predicting response to therapy in individuals harboring a PIK3CA or PTEN aberration. The rate of stable disease ≥6 months/partial response reached 45% in a subgroup of individuals with H1047R PIK3CA mutations. Aberrations in the PI3K/AKT/mTOR pathway are common and potentially actionable in patients with diverse advanced cancers. This work provides further important clinical validation for continued and accelerated use of biomarker-driven trials incorporating rational drug combinations.
    Cell Reports 01/2014; 6(2). DOI:10.1016/j.celrep.2013.12.035 · 8.36 Impact Factor
Show more