PTEN-deficient cancers depend on PIK3CB Export

@article{citeulike:3334573, abstract = {10.1073/pnas.0802655105 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, . Tumors harboring activated p110α, the protein product of , require p110α 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 p110α 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, , , and , to determine which PI3K isoforms are responsible for driving the abnormal proliferation of PTEN-deficient cancers. Down-regulation of in colorectal cancer cells harboring mutations in inhibited downstream PI3K signaling and cell growth. Surprisingly, depletion affected neither PI3K signaling nor cell growth in 3 PTEN-deficient cancer cell lines. In contrast, down-regulation of the isoform, which encodes p110β, resulted in pathway inactivation and subsequent inhibition of growth in both cell-based and settings. This essential function of in PTEN-deficient cancer cells required its lipid kinase activity. Our findings demonstrate that although p110α activation is required to sustain the proliferation of established -mutant tumors, PTEN-deficient tumors are dependent instead on p110β signaling. This unexpected finding demonstrates the need to tailor therapeutic approaches to the genetic basis of PI3K pathway activation to achieve optimal treatment response.}, author = {Wee, Susan and Wiederschain, Dmitri and Maira, Sauveur-Michel and Loo, Alice and Miller, Christine and Debeaumont, Rosalie and Stegmeier, Frank and Yao, Yung-Mae and Lengauer, Christoph}, citeulike-article-id = {3334573}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0802655105}, citeulike-linkout-1 = {http://www.pnas.org/content/105/35/13057.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/105/35/13057.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/18755892}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=18755892}, day = {2}, doi = {10.1073/pnas.0802655105}, journal = {Proceedings of the National Academy of Sciences}, keywords = {cancer, colorectal}, number = {35}, pages = {13057--13062}, posted-at = {2008-09-25 03:53:33}, priority = {0}, title = {PTEN-deficient cancers depend on PIK3CB}, url = {http://dx.doi.org/10.1073/pnas.0802655105}, volume = {105}, year = {2008} }

TY - JOUR ID - citeulike:3334573 L3 - citeulike-article-id:3334573 N2 - 10.1073/pnas.0802655105 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, . Tumors harboring activated p110α, the protein product of , require p110α 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 p110α 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, , , and , to determine which PI3K isoforms are responsible for driving the abnormal proliferation of PTEN-deficient cancers. Down-regulation of in colorectal cancer cells harboring mutations in inhibited downstream PI3K signaling and cell growth. Surprisingly, depletion affected neither PI3K signaling nor cell growth in 3 PTEN-deficient cancer cell lines. In contrast, down-regulation of the isoform, which encodes p110β, resulted in pathway inactivation and subsequent inhibition of growth in both cell-based and settings. This essential function of in PTEN-deficient cancer cells required its lipid kinase activity. Our findings demonstrate that although p110α activation is required to sustain the proliferation of established -mutant tumors, PTEN-deficient tumors are dependent instead on p110β signaling. This unexpected finding demonstrates the need to tailor therapeutic approaches to the genetic basis of PI3K pathway activation to achieve optimal treatment response. IS - 35 JF - Proceedings of the National Academy of Sciences EP - 13062 TI - PTEN-deficient cancers depend on PIK3CB VL - 105 SP - 13057 KW - cancer KW - colorectal AU - Wee, Susan AU - Wiederschain, Dmitri AU - Maira, Sauveur-Michel AU - Loo, Alice AU - Miller, Christine AU - Debeaumont, Rosalie AU - Stegmeier, Frank AU - Yao, Yung-Mae AU - Lengauer, Christoph PY - 2008//02/ UR - http://dx.doi.org/10.1073/pnas.0802655105 ER -