Requirement for interaction of PI3-kinase p110α with RAS in lung tumor maintenance.
RAS proteins directly activate PI3-kinases. Mice bearing a germline mutation in the RAS binding domain of the p110α subunit of PI3-kinse are resistant to the development of RAS-driven tumors. However, it is unknown whether interaction of RAS with PI3-kinase is required in established tumors. The need for RAS interaction with p110α in the maintenance of mutant Kras-driven lung tumors was explored using an inducible mouse model. In established tumors, removal of the ability of p110α to interact with RAS causes long-term tumor stasis and partial regression. This is a tumor cell-autonomous effect, which is improved significantly by combination with MEK inhibition. Total removal of p110α expression or activity has comparable effects, albeit with greater toxicities.
Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Esther
E
Castellano
Clare
C
Sheridan
May Zaw
MZ
Thin
Emma
E
Nye
Bradley
B
Spencer-Dene
Markus E
ME
Diefenbacher
Christopher
C
Moore
Madhu S
MS
Kumar
Miguel M
MM
Murillo
Eva
E
Grönroos
Francois
F
Lassailly
Gordon
G
Stamp
Julian
J
Downward
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D047368:Tumor Burden
D018931:Antineoplastic Agents, Hormonal; D011728:Pyridones; D011744:Pyrimidinones; D013629:Tamoxifen; C560077:trametinib; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)