Single copies of mutant KRAS and mutant PIK3CA Cooperate in immortalized human epithelial cells to induce tumor formation

Grace M. Wang, Hong Yuen Wong, Hiroyuki Konishi, Brian G. Blair, Abde M. Abukhdeir, John P. Gustin, D. Marc Rosen, Samuel Ray Denmeade, Zeshaan Rasheed, William Matsui, Joseph P. Garay, Morassa Mohseni, Michaela J. Higgins, Justin Cidado, Danijela Jelovac, Sarah Croessmann, Rory L. Cochran, Sivasundaram Karnan, Yuko Konishi, Akinobu OtaYoshitaka Hosokawa, Pedram Argani, Josh Lauring, Ben Ho Park

Research output: Contribution to journalArticle

Abstract

The selective pressures leading to cancers with mutations in both KRAS and PIK3CA are unclear. Here, we show that somatic cell knockin of both KRAS G12V and oncogenic PIK3CA mutations in human breast epithelial cells results in cooperative activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in vitro, and leads to tumor formation in immunocompromised mice. Xenografts from doubleknockin cells retain single copies of mutant KRAS and PIK3CA, suggesting that tumor formation does not require increased copy number of either oncogene, and these results were also observed in human colorectal cancer specimens. Mechanistically, the cooperativity between mutant KRAS and PIK3CA is mediated in part by Ras/ p110α binding, as inactivating point mutations within the Ras-binding domain of PIK3CA significantly abates pathway signaling. In addition, Pdk1 activation of the downstream effector p90RSK is also increased by the combined presence of mutant KRAS and PIK3CA. These results provide new insights into mutant KRAS function and its role in carcinogenesis.

Original languageEnglish (US)
Pages (from-to)3248-3261
Number of pages14
JournalCancer Research
Volume73
Issue number11
DOIs
StatePublished - Jun 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Wang, G. M., Wong, H. Y., Konishi, H., Blair, B. G., Abukhdeir, A. M., Gustin, J. P., Rosen, D. M., Denmeade, S. R., Rasheed, Z., Matsui, W., Garay, J. P., Mohseni, M., Higgins, M. J., Cidado, J., Jelovac, D., Croessmann, S., Cochran, R. L., Karnan, S., Konishi, Y., ... Park, B. H. (2013). Single copies of mutant KRAS and mutant PIK3CA Cooperate in immortalized human epithelial cells to induce tumor formation. Cancer Research, 73(11), 3248-3261. https://doi.org/10.1158/0008-5472.CAN-12-1578