Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors

We examined the effects of an inhibitor of PI3K, XL147, against human breast cancer cell lines with constitutive PI3K activation. Treatment with XL147 resulted in dose-dependent inhibition of cell growth and levels of pAKT and pS6, signal transducers in the PI3K/AKT/TOR pathway. In HER2-overexpressing cells, inhibition of PI3K was followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors suppressed the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2+ cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts. These data suggest that PI3K antagonists will inhibit AKT and relieve suppression of receptor tyrosine kinase expression and their activity. Relief of this feedback limits the sustained inhibition of the PI3K/AKT pathway and attenuates the response to these agents. As a result, PI3K pathway inhibitors may have limited clinical activity overall if used as single agents. In patients with HER2-overexpressing breast cancer, PI3K inhibitors should be used in combination with HER2/HER3 antagonists.

[1]  F. Maurer,et al.  The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Daniela Gabriel,et al.  Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity , 2008, Molecular Cancer Therapeutics.

[3]  J. Engelman,et al.  H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation via heregulin production and activation of HER3 , 2010, Oncogene.

[4]  A. Martelli,et al.  Intranuclear 3'-phosphoinositide metabolism and Akt signaling: new mechanisms for tumorigenesis and protection against apoptosis? , 2006, Cellular signalling.

[5]  M. Sliwkowski,et al.  Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  N. Hellyer,et al.  Heregulin-dependent Activation of Phosphoinositide 3-Kinase and Akt via the ErbB2/ErbB3 Co-receptor* , 2001, The Journal of Biological Chemistry.

[7]  R. Parsons,et al.  The role of PTEN signaling perturbations in cancer and in targeted therapy , 2008, Oncogene.

[8]  K Y Hui,et al.  A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). , 1994, The Journal of biological chemistry.

[9]  Carlos L. Arteaga,et al.  Transforming Growth Factor (cid:2) Engages TACE and ErbB3 To Activate Phosphatidylinositol-3 Kinase/Akt in ErbB2-Overexpressing Breast Cancer and Desensitizes Cells to Trastuzumab (cid:1) † , 2008 .

[10]  Dhara N. Amin,et al.  Resiliency and Vulnerability in the HER2-HER3 Tumorigenic Driver , 2010, Science Translational Medicine.

[11]  R. Abraham,et al.  Targeting mTOR globally in cancer: Thinking beyond rapamycin , 2009, Cell cycle.

[12]  Ji Luo,et al.  The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism , 2006, Nature Reviews Genetics.

[13]  H. Lane,et al.  Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells , 2009, Proceedings of the National Academy of Sciences.

[14]  M. Sliwkowski,et al.  Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. , 2009, Cancer cell.

[15]  J. Thigpen.  Clinical Activity of Gemcitabine Plus Pertuzumab in Platinum-Resistant Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer , 2011 .

[16]  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.

[17]  Carlos L Arteaga,et al.  Human Breast Cancer Cells Selected for Resistance to Trastuzumab In vivo Overexpress Epidermal Growth Factor Receptor and ErbB Ligands and Remain Dependent on the ErbB Receptor Network , 2007, Clinical Cancer Research.

[18]  S. Hilsenbeck,et al.  Neoadjuvant trastuzumab induces apoptosis in primary breast cancers , 2005, Nature Clinical Practice Oncology.

[19]  Gary Box,et al.  The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer . , 2008, Journal of medicinal chemistry.

[20]  Lewis C. Cantley,et al.  AKT/PKB Signaling: Navigating Downstream , 2007, Cell.

[21]  Gordon B Mills,et al.  mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. , 2006, Cancer research.

[22]  Pier Paolo Pandolfi,et al.  The PTEN–PI3K pathway: of feedbacks and cross-talks , 2008, Oncogene.

[23]  C. Arteaga,et al.  Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. , 2002, Cancer research.

[24]  Xavier Messeguer,et al.  PROMO: detection of known transcription regulatory elements using species-tailored searches , 2002, Bioinform..

[25]  E. Lam,et al.  The emerging roles of forkhead box (Fox) proteins in cancer , 2007, Nature Reviews Cancer.

[26]  Joseph Avruch,et al.  Rheb Binds and Regulates the mTOR Kinase , 2005, Current Biology.

[27]  Zhijian Zhao,et al.  Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. , 2005, Bioorganic & medicinal chemistry letters.

[28]  Joon-Oh Park,et al.  MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling , 2007, Science.

[29]  C. Sawyers,et al.  The phosphatidylinositol 3-Kinase–AKT pathway in human cancer , 2002, Nature Reviews Cancer.

[30]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.

[31]  J. Baselga,et al.  A phase I dose-escalation study of XL147 (SAR245408), a PI3K inhibitor administered orally to patients (pts) with advanced malignancies. , 2010 .

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

[33]  M. Sliwkowski,et al.  A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. , 2008, Cancer research.