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.
authors.affiliation: Max Planck Institute for Neurological Research and Klaus Joachim Zülch Laboratories, Max Planck Society and Medical Faculty, University of Cologne 50931 Cologne, Germany.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Sos
authors.forename: Stefanie
authors.initials: S
authors.lastname: Fischer
authors.forename: Roland
authors.initials: R
authors.lastname: Ullrich
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Heuckmann
authors.forename: Mirjam
authors.initials: M
authors.lastname: Koker
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heynck
authors.forename: Isabel
authors.initials: I
authors.lastname: Stückrath
authors.forename: Jonathan
authors.initials: J
authors.lastname: Weiss
authors.forename: Florian
authors.initials: F
authors.lastname: Fischer
authors.forename: Kathrin
authors.initials: K
authors.lastname: Michel
authors.forename: Aviva
authors.initials: A
authors.lastname: Goel
authors.forename: Lucia
authors.initials: L
authors.lastname: Regales
authors.forename: Katerina A
authors.initials: KA
authors.lastname: Politi
authors.forename: Samanthi
authors.initials: S
authors.lastname: Perera
authors.forename: Matthäus
authors.initials: M
authors.lastname: Getlik
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.forename: Sascha
authors.initials: S
authors.lastname: Ansén
authors.forename: Thomas
authors.initials: T
authors.lastname: Zander
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Hamid
authors.initials: H
authors.lastname: Kashkar
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
authors.forename: Christine
authors.initials: C
authors.lastname: Orr
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.forename: Lori
authors.initials: L
authors.lastname: Friedman
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005838:Genotype; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors