Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer Journal Article
| Authors: | Sos, M. L.; Fischer, S.; Ullrich, R.; Peifer, M.; Heuckmann, J. M.; Koker, M.; Heynck, S.; Stückrath, I.; Weiss, J.; Fischer, F.; Michel, K.; Goel, A.; Regales, L.; Politi, K. A.; Perera, S.; Getlik, M.; Heukamp, L. C.; Ansen, S.; Zander, T.; Beroukhim, R.; Kashkar, H.; Shokati, K. M.; Sellers, W. R.; Rauh, D.; Orr, C.; Hoeflich, K. P.; Friedman, L.; Wong, K. K.; Pao, W.; Thomas, R. K. |
| Article Title: | Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer |
| 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. |
| Keywords: | signal transduction; mitogen activated protein kinase; controlled study; unclassified drug; gene mutation; human cell; placebo; raf protein; cancer combination chemotherapy; drug efficacy; nonhuman; mouse; drug inhibition; apoptosis; enzyme inhibition; mitogen activated protein kinase inhibitor; lung non small cell cancer; epidermal growth factor receptor; epidermal growth factor receptor 2; animal experiment; animal model; genetic variability; genotype; in vivo study; cancer cell culture; enzyme activation; high throughput screening; protein serine threonine kinase; protein tyrosine kinase; phosphatidylinositol 3 kinase; cancer model; cancer genetics; cancer inhibition; chromosome aberration; drug response; genomics; stomach cancer; ras protein; negative feedback; combination therapy; k ras protein; b raf kinase; scatter factor receptor; 2 (4 hydroxyphenyl) 4 morpholinopyrido[3',2':4,5]furo[3,2 d]pyrimidine; cancer genomics; high-throughput cell line screening; oncogene dependency; gdc 0941; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; nras protein; phosphatidylinositol 3 kinase inhibitor |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 106 |
| Issue: | 43 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2009-01-01 |
| Start Page: | 18351 |
| End Page: | 18356 |
| Language: | English |
| DOI: | 10.1073/pnas.0907325106 |
| PROVIDER: | scopus |
| PMCID: | PMC2757399 |
| PUBMED: | 19805051 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 15" - "Export Date: 30 November 2010" - "CODEN: PNASA" - "Source: Scopus" |
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