Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer
- Martin L. Sosa,1,
- Stefanie Fischera,1,
- Roland Ullricha,1,
- Martin Peifera,1,
- Johannes M. Heuckmanna,
- Mirjam Kokera,
- Stefanie Heyncka,
- Isabel Stückratha,
- Jonathan Weissa,
- Florian Fischera,
- Kathrin Michela,
- Aviva Goelb,
- Lucia Regalesb,
- Katerina A. Politib,
- Samanthi Pererac,
- Matthäus Getlikd,
- Lukas C. Heukampe,
- Sascha Ansénf,
- Thomas Zanderf,
- Rameen Beroukhimc,g,
- Hamid Kashkarh,
- Kevan M. Shokati,j,
- William R. Sellersk,
- Daniel Rauhd,
- Christine Orrl,
- Klaus P. Hoeflichl,
- Lori Friedmanl,
- Kwok-Kin Wongc,m,
- William Paon and
- Roman K. Thomasa,d ,f,2
- aMax Planck Institute for Neurological Research and Klaus Joachim Zülch Laboratories, Max Planck Society and Medical Faculty, University of Cologne, Gleueler Strasse 50, 50931 Cologne, Germany;
- bHuman Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021;
- cDepartment of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115;
- dChemical Genomics Center, Max Planck Society, Otto Hahn Strasse 15, 44227 Dortmund, Germany;
- eDepartment of Pathology, University Hospital Bonn Medical School, Sigmund Freud Strasse 25, 53127 Bonn, Germany;
- fDepartment I of Internal Medicine and Center of Integrated Oncology Cologne–Bonn and
- hInstitute for Medical Microbiology, Immunology, and Hygiene, Medical Faculty, University of Cologne, 50924 Cologne, Germany;
- gBroad Institute of Harvard and Massachusetts Institute of Technology, 320 Charles Street, Cambridge, MA 02141;
- iHoward Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, 600 16th Street, San Francisco, CA 94158;
- jDepartment of Chemistry, University of California, Room 419 Latimer Hall, Berkeley, CA 94720;
- kNovartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139;
- lDepartment of Cancer Signaling and Translational Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94070;
- mDepartment of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115; and
- nVanderbilt-Ingram Cancer Center, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232
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Edited by Charles R. Cantor, Sequenom, Inc., San Diego, CA, and approved August 27, 2009
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↵1M.L.S., S.F., R.U., and M.P. contributed equally to this work. (received for review July 6, 2009)
Abstract
In cancer, genetically activated proto-oncogenes often induce “upstream” dependency on the activity of the mutant oncoprotein. Therapeutic inhibition of these activated oncoproteins can induce massive apoptosis of tumor cells, leading to sometimes dramatic tumor regressions in patients. The PI3K and MAPK signaling pathways are central regulators of oncogenic transformation and tumor maintenance. We hypothesized that upstream dependency engages either one of these pathways preferentially to induce “downstream” dependency. Therefore, we analyzed whether downstream pathway dependency segregates by genetic aberrations upstream in lung cancer cell lines. Here, we show by systematically linking drug response to genomic aberrations in non-small-cell lung cancer, as well as in cell lines of other tumor types and in a series of in vivo cancer models, that tumors with genetically activated receptor tyrosine kinases depend on PI3K signaling, whereas tumors with mutations in the RAS/RAF axis depend on MAPK signaling. However, efficacy of downstream pathway inhibition was limited by release of negative feedback loops on the reciprocal pathway. By contrast, combined blockade of both pathways was able to overcome the reciprocal pathway activation induced by inhibitor-mediated release of negative feedback loops and resulted in a significant increase in apoptosis and tumor shrinkage. Thus, by using a systematic chemo-genomics approach, we identify genetic lesions connected to PI3K and MAPK pathway activation and provide a rationale for combined inhibition of both pathways. Our findings may have implications for patient stratification in clinical trials.
Footnotes
- 2To whom correspondence should be addressed. E-mail: nini{at}nf.mpg.de
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Author contributions: M.L.S., S.F., R.U., M.P., M.K., S.H., I.S., J.W., K.M., A.G., L.R., K.A.P., S.P., L.C.H., T.Z., R.B., H.K., C.O., K.P.H., L.F., K.-K.W., W.P., and R.K.T. designed research; M.L.S., S.F., R.U., J.M.H., M.K., S.H., I.S., J.W., F.F., K.M., A.G., L.R., K.A.P., S.P., H.K., C.O., and K.P.H. performed research; M.G., K.M.S., D.R., and L.F. contributed new reagents/analytic tools; M.L.S., S.F., R.U., M.P., J.M.H., M.K., S.H., J.W., F.F., K.M., A.G., L.R., K.A.P., S.P., M.G., L.C.H., S.A., T.Z., R.B., H.K., K.M.S., W.R.S., D.R., C.O., K.P.H., L.F., K.-K.W., W.P., and R.K.T. analyzed data; and M.L.S., S.F., M.P., S.A., W.R.S., D.R., K.-K.W., W.P., and R.K.T. wrote the paper.
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Conflict of interest statement: R.K.T. has received research support from AstraZeneca and Novartis. W.R.S. is an employee of Novartis. C.O., K.P.H., and L.F. are employees of Genentech.
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This article is a PNAS Direct Submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0907325106/DCSupplemental.
