Drugging PI3K in cancer: refining targets and therapeutic strategies

Highlights • PI3K is an important target for innovative anticancer drug development and precision medicine.• Over 30 small molecule PI3K inhibitors are currently in clinical trial testing.• These drugs include dual PI3K/mTOR, pan-Class I PI3K and isoform-selective PI3K inhibitors.• The PI3Kδ inhibitor idelalisib has received FDA approval for the treatment of B-cell malignancies.• Drug resistance, patient selection and development of targeted combinations remain challenges.

[1]  R. Neve,et al.  Amphiregulin and PTEN evoke a multimodal mechanism of acquired resistance to PI3K inhibition , 2014, Genes & cancer.

[2]  G. Mills,et al.  Oncogenic PIK 3 CA-driven mammary tumors frequently recur via PI 3 K pathway – dependent and PI 3 K pathway – independent mechanisms , 2011 .

[3]  G. Mills,et al.  Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. , 2009, Cancer research.

[4]  Charles Swanton,et al.  Intratumor Heterogeneity: Seeing the Wood for the Trees , 2012, Science Translational Medicine.

[5]  J. Baselga,et al.  Combination of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial. , 2013 .

[6]  K. Okkenhaug,et al.  PI3K in lymphocyte development, differentiation and activation , 2003, Nature Reviews Immunology.

[7]  William Pao,et al.  Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer , 2009, Proceedings of the National Academy of Sciences.

[8]  Y. Ishikawa,et al.  Correlating phosphatidylinositol 3-kinase inhibitor efficacy with signaling pathway status: in silico and biological evaluations. , 2010, Cancer research.

[9]  Paul Workman,et al.  Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma , 2009, Cell cycle.

[10]  W. Fung-Leung.  Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signaling and function. , 2011, Cellular signalling.

[11]  A. Zelenetz,et al.  Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. , 2014, The New England journal of medicine.

[12]  P. Workman,et al.  Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941 , 2009, Molecular Cancer Therapeutics.

[13]  Simon T Barry,et al.  Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ. , 2015, Cancer cell.

[14]  D. Fruman,et al.  Phosphoinositide 3-kinase: diverse roles in immune cell activation. , 2004, Annual review of immunology.

[15]  Alice T. Loo,et al.  PTEN-deficient cancers depend on PIK3CB , 2008, Proceedings of the National Academy of Sciences.

[16]  G. Mills,et al.  Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and -independent mechanisms , 2011, Nature Medicine.

[17]  G. Salles,et al.  PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. , 2014, The New England journal of medicine.

[18]  Michael G. Kharas,et al.  PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor–positive breast cancer , 2015, Science Translational Medicine.

[19]  Weiliang Shi,et al.  Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245409 (XL765), a Novel, Orally Administered PI3K/mTOR Inhibitor in Patients with Advanced Solid Tumors , 2014, Clinical Cancer Research.

[20]  P. Pandolfi,et al.  Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. , 2012, Cancer discovery.

[21]  M. Belvin,et al.  Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors. , 2010, Cancer research.

[22]  N. Ilić,et al.  PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis , 2011, Proceedings of the National Academy of Sciences.

[23]  Ying Feng,et al.  Proteomic Markers of DNA Repair and PI3K Pathway Activation Predict Response to the PARP Inhibitor BMN 673 in Small Cell Lung Cancer , 2013, Clinical Cancer Research.

[24]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[25]  Adam A. Margolin,et al.  The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity , 2012, Nature.

[26]  Paul Workman,et al.  Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. , 2008, Current opinion in pharmacology.

[27]  M. Belvin,et al.  Abstract P2-17-01: The PI3K inhibitor GDC-0032 is selectively potent against PIK3CA mutant breast cancer cell lines and tumors , 2013 .

[28]  P. Workman,et al.  Drugging the PI3 kinome , 2006, Nature Biotechnology.

[29]  S. Ramaswamy,et al.  Systematic identification of genomic markers of drug sensitivity in cancer cells , 2012, Nature.

[30]  D. Erdmann,et al.  Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials , 2014, Molecular Cancer Therapeutics.

[31]  J. Baselga,et al.  Abstract LB-147: Combination of the MEK inhibitor, pimasertib (MSC1936369B), and the PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial. , 2013 .

[32]  Paul Workman,et al.  Envisioning the future of early anticancer drug development , 2010, Nature Reviews Cancer.

[33]  P. LoRusso,et al.  Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer , 2014, Investigational New Drugs.

[34]  M. Waterfield,et al.  Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. , 2007, Cancer research.

[35]  M. Loda,et al.  Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. , 2014, Cancer discovery.

[36]  M. Ellis,et al.  Abstract S2-02: The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results , 2015 .

[37]  Borivoj Vojnovic,et al.  Antagonism of EGFR and HER3 Enhances the Response to Inhibitors of the PI3K-Akt Pathway in Triple-Negative Breast Cancer , 2014, Science Signaling.

[38]  Angela Tam,et al.  AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. , 2015, Cancer cell.

[39]  T. Roberts,et al.  PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context , 2014, Proceedings of the National Academy of Sciences.

[40]  Benjamin Haibe-Kains,et al.  Inconsistency in large pharmacogenomic studies , 2013, Nature.

[41]  A. Bilancio,et al.  Signalling by PI3K isoforms: insights from gene-targeted mice. , 2005, Trends in biochemical sciences.

[42]  I. Flinn,et al.  Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory lymphoma. , 2013 .

[43]  M. Belvin,et al.  Predictive Biomarkers of Sensitivity to the Phosphatidylinositol 3′ Kinase Inhibitor GDC-0941 in Breast Cancer Preclinical Models , 2010, Clinical Cancer Research.

[44]  J. Infante,et al.  Targeting PI3 kinase in cancer. , 2015, Pharmacology & therapeutics.

[45]  J. Engelman,et al.  The PI3K pathway as drug target in human cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[46]  Razelle Kurzrock,et al.  A Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors , 2012, Clinical Cancer Research.

[47]  J. Schellens,et al.  Phase I first-in-human study of the PI3 kinase inhibitor GSK2126458 (GSK458) in patients with advanced solid tumors (study P3K112826). , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  N. Rosenfeld,et al.  Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA , 2013, Nature.

[49]  Paul Workman,et al.  Personalized medicine: patient-predictive panel power. , 2012, Cancer cell.

[50]  L. Cantley,et al.  What a tangled web we weave: emerging resistance mechanisms to inhibition of the phosphoinositide 3-kinase pathway. , 2013, Cancer discovery.

[51]  E. Van Cutsem,et al.  A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors , 2014, Clinical Cancer Research.

[52]  Sridhar Ramaswamy,et al.  Patient-derived models of acquired resistance can identify effective drug combinations for cancer , 2014, Science.

[53]  G. Mills,et al.  Promising rationally derived combination therapy with PI3K and CDK4/6 inhibitors. , 2014, Cancer cell.

[54]  T. Yap,et al.  Development of therapeutic combinations targeting major cancer signaling pathways. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  J. Engelman,et al.  Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer. , 2015, Cancer cell.

[56]  Thomas D. Wu,et al.  A comprehensive transcriptional portrait of human cancer cell lines , 2014, Nature Biotechnology.

[57]  Jordi Rodon,et al.  Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245408 (XL147), an Oral Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors , 2013, Clinical Cancer Research.

[58]  Khin Thway,et al.  Dual Blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) Pathways Synergistically Inhibits Rhabdomyosarcoma Cell Growth In Vitro and In Vivo , 2013, Clinical Cancer Research.

[59]  J. Lehár,et al.  CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. , 2014, Cancer cell.

[60]  G. Hampton,et al.  Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer , 2013, Oncogenesis.

[61]  S. Chandarlapaty,et al.  Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling. , 2014, Cancer discovery.

[62]  Lei He,et al.  PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. , 2012, Cancer discovery.

[63]  Jordi Rodon,et al.  Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  J. Ware,et al.  First-in-Human Phase I Study of Pictilisib (GDC-0941), a Potent Pan–Class I Phosphatidylinositol-3-Kinase (PI3K) Inhibitor, in Patients with Advanced Solid Tumors , 2014, Clinical Cancer Research.

[65]  J. Berlin,et al.  451PDPHASE I STUDY OF THE PI3Kα INHIBITOR BYL719, AS A SINGLE AGENT IN PATIENTS WITH ADVANCED SOLID TUMORS (AST). , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[66]  J. Baselga,et al.  NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. , 2008, Cancer research.

[67]  P. Wipf,et al.  Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. , 2004, Molecular cancer therapeutics.

[68]  A. Haegebarth,et al.  BAY 80-6946 Is a Highly Selective Intravenous PI3K Inhibitor with Potent p110α and p110δ Activities in Tumor Cell Lines and Xenograft Models , 2013, Molecular Cancer Therapeutics.

[69]  Nicolai J. Birkbak,et al.  Clonal status of actionable driver events and the timing of mutational processes in cancer evolution , 2015, Science Translational Medicine.

[70]  W. Hahn,et al.  RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. , 2013, The Journal of clinical investigation.

[71]  Sarat Chandarlapaty,et al.  AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. , 2011, Cancer cell.

[72]  P. Workman,et al.  Phosphatidylinositide-3-kinase inhibitors: addressing questions of isoform selectivity and pharmacodynamic/predictive biomarkers in early clinical trials. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[73]  Kwok-Kin Wong,et al.  Targeting the PI3K signaling pathway in cancer. , 2010, Current opinion in genetics & development.

[74]  Matthew J. Oborski,et al.  Phase I study of intravenous PI3K inhibitor BAY 80-6946: Activity in patients (pts) with advanced solid tumors and non-Hodgkin lymphoma treated in MTD expansion cohorts. , 2012 .

[75]  Miyuki Yoshida,et al.  The Selective Class I PI3K Inhibitor CH5132799 Targets Human Cancers Harboring Oncogenic PIK3CA Mutations , 2011, Clinical Cancer Research.

[76]  V. Gandhi,et al.  Idelalisib: First-in-Class PI3K Delta Inhibitor for the Treatment of Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia, and Follicular Lymphoma , 2015, Clinical Cancer Research.