Deregulation of the PI3K signaling pathway is observed in many human
cancers and occurs most frequently through loss of
PTEN phosphatase tumor suppressor function or through somatic activating mutations in the Class IA PI3K, PIK3CA.
Tumors harboring activated p110alpha, the
protein product of PIK3CA, require p110alpha activity for growth and survival and hence are expected to be responsive to inhibitors of its
lipid kinase activity. Whether PTEN-deficient
cancers similarly depend on p110alpha activity to sustain activation of the PI3K pathway has been unclear. In this study, we used a single-vector lentiviral inducible
shRNA system to selectively inactivate the three Class IA PI3Ks, PIK3CA, PIK3CB, and PIK3CD, to determine which PI3K
isoforms are responsible for driving the abnormal proliferation of PTEN-deficient
cancers. Down-regulation of PIK3CA in
colorectal cancer cells harboring mutations in PIK3CA inhibited downstream PI3K signaling and cell growth. Surprisingly, PIK3CA depletion affected neither PI3K signaling nor cell growth in 3 PTEN-deficient
cancer cell lines. In contrast, down-regulation of the PIK3CB
isoform, which encodes p110beta, resulted in pathway inactivation and subsequent inhibition of growth in both cell-based and in vivo settings. This essential function of PIK3CB in PTEN-deficient
cancer cells required its
lipid kinase activity. Our findings demonstrate that although p110alpha activation is required to sustain the proliferation of established PIK3CA-mutant
tumors, PTEN-deficient
tumors are dependent instead on p110beta signaling. This unexpected finding demonstrates the need to tailor therapeutic approaches to the genetic basis of PI3K pathway activation to achieve optimal treatment response.