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Phosphatidylinositol 3-kinases (PI3Ks) represent a large and complex family consisting of three classes with multiple subunits and isoforms. Only class IA PI3Ks have been clearly implicated in human cancer. Class 1A PI3Ks are a collection of p85/p110 heterodimeric lipid kinases that generate lipid second messenger in response to growth factor stimulation and subsequent activation of receptor tyrosine kinases (RTKs). The p110 catalytic subunit consists of three isoforms (a, b and d) that are encoded by the genes PIK3CA, PIK3CB and PIK3CD, respectively. While p110d is primarily found in leukocytes, p110a and p110b are ubiquitously expressed. However, we have very limited understanding of to what extend these p110 isoforms have overlapping or distinct functions. Recently, frequent somatic activating mutations in human cancers have been identified in p110a, but not in p110b, indicating distinct roles for p110a and p110b in cell signaling and oncogenic transformation. It is now apparent that p110a is tumorigenic when it is mutated. But it is not clear that which isoform is important for transmitting oncogenic signals from receptor tyrosine kinases or loss of PTEN function. All class IA PI3Ks display the same sensitivity to the classical PI3K inhibitors wortmannin and LY294002. Mice lacking p110a or p110b are early embryonic lethal. To delineate the roles of p110a or p110b in oncogenic signaling and biological function, we recently generated conditional knockout animals for the PIK3CA and PIK3CB genes via the Cre/loxP recombination system. We have tested the effects of p110a and p110b ablation in MEFs. We find that MEFs lacking p110a are selectively deficient in growth factor signaling while p110b null cells showed no difference from wild type in response to EGF, Insulin or PDGF stimulation. The p110a deficient cells showed markedly decreased responses to EGF and insulin/IGF while displaying wild type responses to PDGF and serum. Moreover, the p110a null MEFs are also resistant to transformation by a number of oncogenic agents, including tumor derived mutant alleles of EGFR, over-expression of IGF1R and polyoma middle T antigen. Our work will facilitate the design of targeting specific component of the PI3K pathway in cancer to maximize the therapeutic window.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]