Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer.
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.
Sos
Martin L
ML
Max Planck Institute for Neurological Research and Klaus Joachim Zülch Laboratories, Max Planck Society and Medical Faculty, University of Cologne 50931 Cologne, Germany.
Fischer
Stefanie
S
Ullrich
Roland
R
Peifer
Martin
M
Heuckmann
Johannes M
JM
Koker
Mirjam
M
Heynck
Stefanie
S
Stückrath
Isabel
I
Weiss
Jonathan
J
Fischer
Florian
F
Michel
Kathrin
K
Goel
Aviva
A
Regales
Lucia
L
Politi
Katerina A
KA
Perera
Samanthi
S
Getlik
Matthäus
M
Heukamp
Lukas C
LC
Ansén
Sascha
S
Zander
Thomas
T
Beroukhim
Rameen
R
Kashkar
Hamid
H
Shokat
Kevan M
KM
Sellers
William R
WR
Rauh
Daniel
D
Orr
Christine
C
Hoeflich
Klaus P
KP
Friedman
Lori
L
Wong
Kwok-Kin
KK
Pao
William
W
Thomas
Roman K
RK
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*
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors