PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers.
The RAS pathway is one of the most frequently deregulated pathways in cancer. RAS signals through multiple effector pathways, including the RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK MAPK and phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascades. The oncogenic potential of these effector pathways is illustrated by the frequent occurrence of activating mutations in BRAF and PIK3CA as well as loss-of-function mutations in the tumor suppressor PTEN, a negative regulator of PI3K. Previous studies have found that whereas BRAF mutant cancers are highly sensitive to MEK inhibition, RAS mutant cancers exhibit a more variable response. The molecular mechanisms responsible for this heterogeneous response remain unclear. In this study, we show that PI3K pathway activation strongly influences the sensitivity of RAS mutant cells to MEK inhibitors. Activating mutations in PIK3CA reduce the sensitivity to MEK inhibition, whereas PTEN mutations seem to cause complete resistance. We further show that down-regulation of PIK3CA resensitizes cells with co-occurring KRAS and PIK3CA mutations to MEK inhibition. At the molecular level, the dual inhibition of both pathways seems to be required for complete inhibition of the downstream mammalian target of rapamycin effector pathway and results in the induction of cell death. Finally, we show that whereas inactivation of either the MEK or PI3K pathway leads to partial tumor growth inhibition, targeted inhibition of both pathways is required to achieve tumor stasis. Our study provides molecular insights that help explain the heterogeneous response of KRAS mutant cancers to MEK pathway inhibition and presents a strong rationale for the clinical testing of combination MEK and PI3K targeted therapies.
Wee
Susan
S
Novartis Institutes for BioMedical Research, Cambridge, MA, USA. susan.wee@bms.com
Jagani
Zainab
Z
Xiang
Kay Xiaoqin
KX
Loo
Alice
A
Dorsch
Marion
M
Yao
Yung-Mae
YM
Sellers
William R
WR
Lengauer
Christoph
C
Stegmeier
Frank
F
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000633:toxicity; D004318:Doxycycline / Q000633:toxicity*; D004789:Enzyme Activation; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D001549:Benzamides; D004159:Diphenylamine; D004318:Doxycycline; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; C506614:mirdametinib