PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling Journal Article
| Authors: | Halilovic, E.; She, Q. B.; Ye, Q.; Pagliarini, R.; Sellers, W. R.; Solit, D. B.; Rosen, N. |
| Article Title: | PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling |
| Abstract: | Mutational activation of KRAS is a common event in human tumors. Identification of the key signaling pathways downstream of mutant KRAS is essential for our understanding of how to pharmacologically target these cancers in patients. We show that PD0325901, a small-molecule MEK inhibitor, decreases MEK/ ERK pathway signaling and destabilizes cyclin D1, resulting in significant anticancer activity in a subset of KRAS mutant tumors in vitro and in vivo. Mutational activation of PIK3CA, which commonly co-occurs with KRAS mutation, provides resistance to MEK inhibition through reactivation of AKT signaling. Genetic ablation of the mutant PIK3CA allele in MEK inhibitor-resistant cells restores MEK pathway sensitivity, and re-expression of mutant PIK3CA reinstates the resistance, highlighting the importance of this mutation in resistance to therapy in human cancers. In KRAS mutant tumors, PIK3CA mutation restores cyclin D1 expression and G1-S cell cycle progression so that they are no longer dependent on KRAS and MEK/ERK signaling. Furthermore, the growth of KRAS mutant tumors with coexistent PIK3CA mutations in vivo is profoundly inhibited with combined pharmacologic inhibition of MEK and AKT. These data suggest that tumors with both KRAS and phosphoinositide 3-kinase mutations are unlikely to respond to the inhibition of the MEK pathway alone but will require effective inhibition of both MEK and phosphoinositide 3-kinase/ AKT pathway signaling. ©2010 AACR. |
| Keywords: | signal transduction; mitogen activated protein kinase; protein kinase b; controlled study; protein expression; unclassified drug; gene mutation; human cell; mutation; proto-oncogene proteins; drug efficacy; nonhuman; pancreatic neoplasms; mouse; animals; mice; animal tissue; cell cycle progression; cell cycle s phase; enzyme inhibition; map kinase signaling system; protein degradation; lung neoplasms; animal experiment; colonic neoplasms; hct116 cells; alleles; antineoplastic activity; cell line, tumor; phosphatidylinositol 3 kinase; cancer inhibition; gene activation; cell growth processes; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; extracellular signal-regulated map kinases; cell cycle arrest; ras proteins; oncogene k ras; tumor growth; cyclin d1; cell cycle g1 phase; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; benzamides; map kinase kinase kinases; phosphatidylinositol 3 kinase ca; diphenylamine; gene knockout techniques |
| Journal Title: | Cancer Research |
| Volume: | 70 |
| Issue: | 17 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2010-09-01 |
| Start Page: | 6804 |
| End Page: | 6814 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-10-0409 |
| PUBMED: | 20699365 |
| PROVIDER: | scopus |
| PMCID: | PMC3178450 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 20 April 2011" - "CODEN: CNREA" - "Source: Scopus" |
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