PI3K pan-inhibition impairs more efficiently proliferation and survival of T-cell acute lymphoblastic leukemia cell lines when compared to isoform-selective PI3K inhibitors

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Francesca Buontempo (Creator)

Alessandra Cappellini (Creator)

Francesca Chiarini (Creator)

Camilla Evangelisti (Creator)

Cecilia Evangelisti (Creator)

Annalisa Lonetti (Creator)

Alberto Maria Martelli (Creator)

James A. McCubrey (Creator)

Ester Orsini (Creator)

Antonino Maria Spartà (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Class I phosphatidylinositol 3-kinases (PI3Ks) are frequently activated in T-cell acute lymphoblastic leukemia (T-ALL), mainly due to the loss of PTEN function. Therefore, targeting PI3Ks is a promising innovative approach for T-ALL treatment, however at present no definitive evidence indicated which is the better therapeutic strategy between pan or selective isoform inhibition, as all the four catalytic subunits might participate in leukemogenesis. Here, we demonstrated that in both PTEN deleted and PTEN non deleted T-ALL cell lines, PI3K pan-inhibition exerted the highest cytotoxic effects when compared to both selective isoform inhibition or dual p110?/d inhibition. Intriguingly, the dual p110?/d inhibitor IPI-145 was effective in Loucy cells, which are representative of early T-precursor (ETP)-ALL, a T-ALL subtype associated with a poor outcome. PTEN gene deletion did not confer a peculiar reliance of T-ALL cells on PI3K activity for their proliferation/survival, as PTEN was inactivated in PTEN non deleted cells, due to posttranslational mechanisms. PI3K pan-inhibition suppressed Akt activation and induced caspase-independent apoptosis. We further demonstrated that in some T-ALL cell lines, autophagy could exert a protective role against PI3K inhibition. Our findings strongly support clinical application of class I PI3K pan-inhibitors in T-ALL treatment, with the possible exception of ETP-ALL cases.

Additional Information

Publication

Other

Oncotarget; 6:12 p. 10399-10414

Language: English

Date: 2015

Keywords

PI3K isoforms, targeted therapy, T-ALL, PTEN, autophagy

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