Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer Export

@article{citeulike:6016946, abstract = {10.1073/pnas.0907325106 In cancer, genetically activated proto-oncogenes often induce \^{a}€œ\^{a}€ 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 dependency engages either one of these pathways preferentially to induce \^{a}€œ\^{a}€ dependency. Therefore, we analyzed whether pathway dependency segregates by genetic aberrations 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 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.}, author = {Sos, Martin L. and Fischer, Stefanie and Ullrich, Roland and Peifer, Martin and Heuckmann, Johannes M. and Koker, Mirjam and Heynck, Stefanie and St\~{A}¼ckrath, Isabel and Weiss, Jonathan and Fischer, Florian and Michel, Kathrin and Goel, Aviva and Regales, Lucia and Politi, Katerina A. and Perera, Samanthi and Getlik, Matth\~{A}¤us and Heukamp, Lukas C. and Ans\~{A}{\copyright}n, Sascha and Zander, Thomas and Beroukhim, Rameen and Kashkar, Hamid and Shokat, Kevan M. and Sellers, William R. and Rauh, Daniel and Orr, Christine and Hoeflich, Klaus P. and Friedman, Lori and Wong, Kwok-Kin and Pao, William and Thomas, Roman K.}, citeulike-article-id = {6016946}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0907325106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/43/18351.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/43/18351.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19805051}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19805051}, day = {27}, doi = {10.1073/pnas.0907325106}, journal = {Proceedings of the National Academy of Sciences}, keywords = {cancer, genome, inhibition, mapk, pathway, pi3k}, month = {October}, number = {43}, pages = {18351--18356}, posted-at = {2009-10-27 22:18:36}, priority = {2}, title = {Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer}, url = {http://dx.doi.org/10.1073/pnas.0907325106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:6016946 L3 - citeulike-article-id:6016946 N2 - 10.1073/pnas.0907325106 In cancer, genetically activated proto-oncogenes often induce “” 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 dependency engages either one of these pathways preferentially to induce “” dependency. Therefore, we analyzed whether pathway dependency segregates by genetic aberrations 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 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. IS - 43 JF - Proceedings of the National Academy of Sciences EP - 18356 TI - Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer VL - 106 SP - 18351 KW - cancer KW - genome KW - inhibition KW - mapk KW - pathway KW - pi3k AU - Sos, Martin AU - Fischer, Stefanie AU - Ullrich, Roland AU - Peifer, Martin AU - Heuckmann, Johannes AU - Koker, Mirjam AU - Heynck, Stefanie AU - Stückrath, Isabel AU - Weiss, Jonathan AU - Fischer, Florian AU - Michel, Kathrin AU - Goel, Aviva AU - Regales, Lucia AU - Politi, Katerina AU - Perera, Samanthi AU - Getlik, Matthäus AU - Heukamp, Lukas AU - Ansén, Sascha AU - Zander, Thomas AU - Beroukhim, Rameen AU - Kashkar, Hamid AU - Shokat, Kevan AU - Sellers, William AU - Rauh, Daniel AU - Orr, Christine AU - Hoeflich, Klaus AU - Friedman, Lori AU - Wong, Kwok-Kin AU - Pao, William AU - Thomas, Roman PY - 2009/10/27/ UR - http://dx.doi.org/10.1073/pnas.0907325106 ER -