Proliferation of <scp>PTEN</scp>‐deficient haematopoietic tumour cells is not affected by isoform‐selective inhibition of p110β <scp>PI</scp>3‐kinase and requires blockade of all class 1 <scp>PI</scp>3K activity

Stengel, Chloe; Jenner, Emma; Meja, Koremu; Mayekar, Saloni; Khwaja, Asim

doi:10.1111/bjh.12353

Cited by 16 publications

(14 citation statements)

References 9 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The pan-inhibitor BKM-120 has been evaluated in both preclinical hematologic and solid tumor models [ 17 , 18 ] and phase I clinical trials [ 19 – 21 ], whereas ZSTK-474 [ 22 – 24 ] and PIK-90 [ 15 ] efficacy has been assessed only in preclinical models. To specifically inhibit p110α, p110β, p110δ, and p110γ we employed A-66, TGX-221, CAL-101, and AS-605240, respectively, whose selectivity has been reported elsewhere [ 14 , 15 , 25 ], and that, at least in several instances, have shown effectiveness in hematological malignancies [ 26 ]. Because of the prominent role of p110δ and p110γ isoforms in T-lymphocytes [ 5 ], effects of the γ/δ dual inhibitor IPI-145, as well as of a combination consisting of CAL-101 and AS-605240 were also evaluated.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, in human T-ALL cells devoid of PTEN, pharmacological blockade of both p110γ and p110δ impacted on tumor cell proliferation and survival, supporting the relevance of these isoforms as therapeutic targets for T-ALL treatment [ 14 ]. On the contrary, a more recent study highlighted the importance of blocking all class I PI3K isoforms to efficiently inhibit cell proliferation in PTEN deficient T-ALL cell lines [ 15 ]. However, in T-ALL patients PTEN genomic alterations are low frequency events, as PTEN gene deletions and mutations predicted to cause protein truncation occur collectively in about 10% of T-ALL cases [ 11 , 12 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2015

View full text Add to dashboard Cite

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 p110γ/δ inhibition. Intriguingly, the dual p110γ/δ 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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Specific inhibitors of p110b typically show far greater potency against PTENdeficient cell lines than PIK3CA-mutant lines, both in vitro and in vivo (34,35). However, in vitro experiments comparing the various classes of PI3K inhibitor suggest that simultaneous p110a and p110b inhibition (or in some circumstances complete blockade of all class I PI3K activity) may be required for optimal growth inhibition in certain PTEN-deficient malignancies, including endometrial cancer and lymphoblastic leukemia (36)(37)(38). Such observations may point to a redundancy in isoform-specific signaling, which suggests that in certain contexts, inhibition of one PI3K isoform may be offset by the increased activity of others.…”

Section: P110b Inhibitors: Necessary and Sufficient For Controlling Pmentioning

confidence: 99%

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

Dienstmann¹,

Rodón²,

Serra³

et al. 2014

Molecular Cancer Therapeutics

387

331

View full text Add to dashboard Cite

The frequent activation of the PI3K/AKT/mTOR pathway in cancer, and its crucial role in cell growth and survival, has made it a much desired target for pharmacologic intervention. Following the regulatory approval of the rapamycin analogs everolimus and temsirolimus, recent years have seen an explosion in the number of phosphoinositide 3-kinase (PI3K) pathway inhibitors under clinical investigation. These include: ATPcompetitive, dual inhibitors of class I PI3K and mTORC1/2; "pan-PI3K" inhibitors, which inhibit all four isoforms of class I PI3K (a, b, d, g); isoform-specific inhibitors of the various PI3K isoforms; allosteric and catalytic inhibitors of AKT; and ATP-competitive inhibitors of mTOR only (and thus mTORC1 and mTORC2). With so many agents in development, clinicians are currently faced with a wide array of clinical trials investigating a multitude of inhibitors with different mechanisms of action, being used both as single agents and in combination with other therapies. Here, we provide a review of the literature, with the aim of differentiating the genomic contexts in which these various types of inhibitors may potentially have superior activity.

show abstract

“…In PTEN-deficient solid cancers (of the brain, breast and prostate), isoform specific RNA interference identified PI3Kβ as essential for cellular growth [ 53 ], but in PTEN deficient T-ALL subtype specific in vitro inhibition of PI3Kβ failed to effectively inhibit downstream signaling of the PI3K/AKT/mTOR network [ 54 ]. In a mouse model of T-ALL with PTEN deficiency, both PI3Kδ and PI3Kγ supported leukemogenesis and additional silencing of these two isoforms of PI3K was capable of suppressing tumor formation [ 55 ].…”

Section: Reviewmentioning

confidence: 99%

Outlook on PI3K/AKT/mTOR inhibition in acute leukemia

2015

View full text Add to dashboard Cite

Technological advances allowing high throughput analyses across numerous cancer tissues have allowed much progress in understanding complex cellular signaling. In the future, the genetic landscape in cancer may have more clinical relevance than diagnosis based on tumor origin. This progress has emphasized PI3K/AKT/mTOR, among others, as a central signaling center of cancer development due to its governing control in cellular growth, survival, and metabolism. The discovery of high frequencies of mutations in the PI3K/AKT/mTOR pathway in different cancer entities has sparked interest to inhibit elements of this pathway. In acute leukemia pharmacological interruption has yet to achieve desirable efficacy as targetable downstream mutations in PI3K/AKT/mTOR are absent. Nevertheless, mutations in membrane-associated genes upstream of PI3K/AKT/mTOR are frequent in acute leukemia and are associated with aberrant activation of PI3K/AKT/mTOR thus providing a good rationale for further exploration. This review attempts to summarize key findings leading to aberrant activation and to reflect on both promises and challenges of targeting PI3K/AKT/mTOR in acute leukemia. Our emphasis lies on the insights gained through high-throughput data acquisition that open up new avenues for identifying specific subgroups of acute leukemia as ideal candidates for PI3K/AKT/mTOR targeted therapy.

show abstract

Proliferation of PTEN‐deficient haematopoietic tumour cells is not affected by isoform‐selective inhibition of p110β PI3‐kinase and requires blockade of all class 1 PI3K activity

Cited by 16 publications

References 9 publications

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

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

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

Outlook on PI3K/AKT/mTOR inhibition in acute leukemia

Contact Info

Product

Resources

About