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Activity of any class IA PI3K isoform can sustain cell proliferation and survival

Foukas, LC; Berenjeno, IM; Gray, A; Khwaja, A; Vanhaesebroeck, B; (2010) Activity of any class IA PI3K isoform can sustain cell proliferation and survival. P NATL ACAD SCI USA , 107 (25) 11381 - 11386. 10.1073/pnas.0906461107.

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Abstract

Small molecule inhibitors of PI3K for oncology mainly target the class I PI3Ks, comprising the p110 alpha, beta, gamma, and delta isoforms, of which only p110 alpha is mutated in cancer. To assess the roles of class I PI3K isoforms in cell proliferation and survival, we generated immortalized mouse leukocyte and fibroblast models in which class I PI3Ks were inactivated by genetic and pharmacological approaches. In IL3-dependent hemopoietic progenitor cells (which express all four class I PI3K isoforms), genetic inactivation of either p110 alpha or p110 delta did not affect cell proliferation or survival or sensitize to p110 beta or p110 gamma inactivation. Upon compound inactivation of p110 alpha and p110 delta, which removed >90% of p85-associated PI3K activity, remarkably, cells continued to proliferate effectively, with p110 beta assuming an essential role in signaling and cell survival. Furthermore, under these conditions of diminished class I PI3K activity, input from the ERK pathway became important for cell survival. Similar observations were made in mouse embryonic. broblasts (which mainly express p110 alpha and p110 beta) in which p110 alpha or p110 beta could sustain cell proliferation as a single isoform. Taken together, these data demonstrate that a small fraction of total class I PI3K activity is sufficient to sustain cell survival and proliferation. Persistent inhibition of selected PI3K isoforms can allow the remaining isoform( s) to couple to upstream signaling pathways in which they are not normally engaged. Such functional redundancy of class IA PI3K isoforms upon sustained PI3K inhibition has implications for the development and use of PI3K inhibitors in cancer.

Type: Article
Title: Activity of any class IA PI3K isoform can sustain cell proliferation and survival
DOI: 10.1073/pnas.0906461107
Keywords: apoptosis, cancer therapeutics, inhibitors, combination therapy, MAP kinase, PHOSPHOINOSITIDE 3-KINASE, PHOSPHATIDYLINOSITOL 3-KINASE, ONCOGENIC TRANSFORMATION, P110-ALPHA ISOFORM, INDUCED APOPTOSIS, PROTEIN-KINASE, GROWTH, INHIBITION, CANCER, P110-BETA
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/119637
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