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PIK3CA Cooperates with Other Phosphatidylinositol 3'-Kinase Pathway Mutations to Effect Oncogenic Transformation

¹ Cancer Research Institute and ² Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California; ³ Department of Obstetrics and Gynecology, University of Tokyo, Tokyo, Japan; and ⁴ Department of Clinical Cytology, Kitasato University Graduate School of Medical Sciences, Kanagawa, Japan

Requests for reprints: Katsutoshi Oda, Department of Obstetrics and Gynecology, University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-5800-8657; Fax: 81-3-3816-2017; E-mail: katsutoshi-tky{at}umin.ac.jp.

Key Words: PIK3CA mutation • coexistent alterations • oncogenic transformation

Mutations in genes functioning in different pathways frequently occur together in the same cancer, whereas mutations in the same pathway tend to be mutually exclusive. However, the majority of colon, breast, and endometrial cancers that possess mutations in PIK3CA, the catalytic subunit p110 of phosphatidylinositol 3'-kinase (PI3K), also possess mutations or alterations in genes upstream of PI3K such as Ras, ERBB2/ERBB3, or PTEN. PIK3CA mutations occur almost exclusively in invasive tumors, whereas upstream mutations occur as frequently in early-stage and late-stage tumors, suggesting that PIK3CA mutation is a late-stage event that may augment earlier activation of the PI3K pathway. Consistent with this, we find that levels of p-AKT (Ser⁴⁷³) induced by mutant Ras or knockdown of PTEN were dramatically increased by addition of mutant PIK3CA. Soft agar assays revealed that anchorage-independent growth induced by mutant Ras was greatly increased in the presence of mutant PIK3CA. In breast, colon, and endometrial cancers in which the PI3K pathway is activated by a combination of mutant PIK3CA and alterations in Ras, ERBB2/3, or PTEN, signaling to downstream elements such as Akt was mediated exclusively by the p110 isoform, rather than a combination of different PI3K isoforms. Our data therefore suggest that in tumors with co-occurring mutations in multiple components of the PI3K pathway, selective inhibition of the isoform of p110 is an attractive therapeutic strategy, especially for late-stage tumors. [Cancer Res 2008;68(19):8127–36]

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