Antitumor Efficacy of PKI-587, a Highly Potent Dual PI3K/mTOR Kinase Inhibitor

Mallon, Robert; Feldberg, Larry; Lucas, Judy; Chaudhary, Inder; Dehnhardt, Christoph M.; Santos, Efren Delos; Chen, Zecheng; Santos, Osvaldo Dos; Ayral‐Kaloustian, Semiramis; Venkatesan, Aranapakam M.; Hollander, Irwin

doi:10.1158/1078-0432.ccr-10-1694

Cited by 154 publications

(126 citation statements)

References 48 publications

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“…In preclinical models, inhibiting the PI3K pathway showed synergy with cytotoxic agents, enhancing its efficacy by potentiating apoptosis (41). In addition, dual inhibition of the RAF/MEK and PI3K/AKT/mTOR pathways seems to be required for complete abrogation of downstream effectors in RASmutant tumors (19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Dienstmann

Serpico

Rodón

et al. 2012

Molecular Cancer Therapeutics

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Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in phase I trials with targeted therapies will improve the outcomes of patients with cancer. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for specific aberrations (KRAS/BRAF/PIK3CA mutations, PTEN and pMET expression). Patients were subsequently offered phase I trials with matched targeted agents (MTA) directed at the identified anomalies. During 2010 and 2011, tumor molecular analysis was conducted in 254 patients: KRAS mutations (80 of 254, 31.5%), BRAF mutations (24 of 196, 12.2%), PIK3CA mutations (15 of 114, 13.2%), KRAS and PIK3CA mutations (9 of 114, 7.9%), low PTEN expression (97 of 183, 53.0%), and high pMET expression (38 of 64, 59.4%). In total, 68 patients received 82 different MTAs: phosphoinositide 3-kinase (PI3K) pathway inhibitor (if PIK3CA mutation, n ¼ 10; or low PTEN, n ¼ 32), PI3K pathway inhibitor plus MEK inhibitor (if KRAS mutation, n ¼ 10; or BRAF mutation, n ¼ 1), second-generation anti-EGF receptor monoclonal antibodies (if wild-type KRAS, n ¼ 11), anti-hepatocyte growth factor monoclonal antibody (if high pMET, n ¼ 10), mTOR inhibitor plus anti-insulin-like growth factor-1 receptor monoclonal antibody (if low PTEN, n ¼ 5), and BRAF inhibitor (if BRAF mutation, n ¼ 3). Median time-to-treatment failure on MTA was 7.9 versus 16.3 weeks for their prior systemic antitumor therapy (P < 0.001). Partial response was seen in 1 patient [1.2%, PI3K inhibitor with PIK3CA mutation] and stable disease >16 weeks in 10 cases (12.2%). These results suggest that matching chemorefractory patients with colorectal cancer with targeted agents in phase I trials based on the current molecular profile does not confer a significant clinical benefit. Mol Cancer Ther; 11(9); 2062-71. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 99%

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Dienstmann

Serpico

Rodón

et al. 2012

Molecular Cancer Therapeutics

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“…GSK2126458 and PKI-587 are highly selective and potent small-molecule inhibitors which could effectively suppress both multiple class I PI3K isoforms and mTOR kinase activity (24,25). GSK2126458 has been identified as a highly potent, orally bioavailable inhibitor of p110a, p110b, p110g, p110d, mTORC1, and mTORC2.…”

Section: Introductionmentioning

confidence: 99%

“…PKI-587 is a highly potent dual inhibitor of PI3Ka, PI3Kg, and mTOR. Preclinical studies have demonstrated potent inhibitory effects of PKI-587 on a variety of human cancer cell lines, such as breast, glioma, lung, melanoma, colon, and liver cancer (25,26). Because PKI-587 has strong antitumor activity in vitro and in xenograft models, it is currently being evaluated in a phase I clinical trial in patients with solid tumors (NCT00940498).…”

Section: Introductionmentioning

confidence: 99%

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

Liu

Sun

et al. 2015

Molecular Cancer Therapeutics

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Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI-587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual g-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR).Both GSK216458 and PKI-587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration-and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G 2 -M cellcycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC. Mol Cancer Ther; 14(2); 429-39. Ó2014 AACR.

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“…This molecular knowledge has stimulated the development of news inhibitors termed dual PI3K-mTOR inhibitors that include NVP-BEZ235, XL765, BGT226, PI-103, PF-04691502, PKI-587 and GDC-0980 [142][143][144][145][146][147][148]. Comparing with the other types of PI3K pathway inhibitors, dual PI3KmTOR inhibitors have the possible advantage of inhibiting all PI3K catalytic isoforms, mTORC1 and mTORC2 [6].…”

Section: Dual Mtor/ Pi3k Inhibitorsmentioning

confidence: 99%

“…Comparing with the other types of PI3K pathway inhibitors, dual PI3KmTOR inhibitors have the possible advantage of inhibiting all PI3K catalytic isoforms, mTORC1 and mTORC2 [6]. The catalytic sites of PI3K and mTOR share a high degree of sequence homology, thus enabling the abrogation of the catalytic activity of both PI3K and mTOR, consequently blocking downstream signaling related to cell proliferation, survival, and angiogenesis [142][143][144][145]. Therefore, these inhibitors may effectively turn off this pathway completely and display best efficacy in feedback inhibition normally observed with mTORC1 inhibitors [149].…”

Section: Dual Mtor/ Pi3k Inhibitorsmentioning

confidence: 99%

Metformin and mTOR Inhibitors: Allies against Ovarian and Breast Cancers

Guimarães¹,

Tessarollo²,

Santos³

et al. 2017

J Carcinog Mutagen

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Cancer is one of the leading causes of death worldwide. Every year 8.2 million people die from the disease. In this context, breast and ovarian cancer are the most incidental among women. Elucidation of cell growth pathways and the observation that these pathways are altered in human cancer have encouraged the search for specific inhibitors. The phosphatidylinositol-3cinase (PI3K)/Protein kinase b (AKT)/Mammalian Target of Rapamycin (mTOR) is an important pathway involved in cell growth, tumorigenesis, cell invasion, and resistance to therapies. This pathway is often activated in breast and ovarian cancers and the deregulation of its signaling can contribute to tumor growth, angiogenesis and metastasis. Metformin is one of the most commonly prescribed antidiabetic drugs in the world whose anticancer effects, mediated by reduced mTOR signaling, have become notable. Therefore, this review provides an overview of signaling pathway PI3K/AKT/mTOR in the ovarian and breast cancers as well as for target therapies of mTOR signaling, with an emphasis on its mechanisms, clinical applicability and future perspectives.

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Antitumor Efficacy of PKI-587, a Highly Potent Dual PI3K/mTOR Kinase Inhibitor

Cited by 154 publications

References 48 publications

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

Metformin and mTOR Inhibitors: Allies against Ovarian and Breast Cancers

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