<scp>PI</scp>3K‐dependent multiple myeloma cell survival is mediated by the <scp>PIK</scp>3<scp>CA</scp> isoform

Hofmann, Claudia; Stühmer, Thorsten; Schmiedl, Nadine; Wetzker, Reinhard; Mottok, Anja; Rosenwald, Andreas; Langer, Christian; Zovko, Josip; Chatterjee, Manik; Einsele, Hermann; Bargou, Ralf C.; Steinbrunn, Torsten

doi:10.1111/bjh.12920

Cited by 19 publications

(28 citation statements)

References 57 publications

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“…The discrepant cytotoxicity of copanlisib and GDC‐0941 for CLL cells despite a similar ratio of biochemical p110‐δ and p110‐α inhibition can be explained by the higher absolute potency of copanlisib for inhibiting these isoforms. In agreement with comparisons of inhibitor cytotoxicity for CLL and MCL cells with isoform selectivity profiles, RNA interference revealed that the survival of myeloma cell lines strongly depended on p110‐alpha . In contrast, co‐culture‐induced Akt phosphorylation of myeloma cells was reduced much more strongly by knock‐down of p110‐ δ than of p110‐α .…”

Section: Discussionsupporting

confidence: 65%

“…In agreement with comparisons of inhibitor cytotoxicity for CLL and MCL cells with isoform selectivity profiles, RNA interference revealed that the survival of myeloma cell lines strongly depended on p110alpha. 42 In contrast, co-culture-induced Akt phosphorylation of myeloma cells was reduced much more strongly by knockdown of p110-d than of p110-a. 43 Taken together we show that the dual p110-a and p110-d-selective inhibitor copanlisib leads to remarkable, potentially clinically useful inhibition of the survival of CLL cells, which by far surpasses that by idelalisib and duvelisib, as well as by other pan-class IA inhibitors.…”

Section: Discussionmentioning

confidence: 96%

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Efficacy of phosphatidylinositol‐3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells

Göckeritz

Kerwien

Baumann

et al. 2015

Intl Journal of Cancer

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Pharmacological inhibition of phosphatiylinositide-3-kinase (PI3K)-mediated signaling holds great promise for treating chronic lymphocytic leukemia (CLL). Therefore we assessed three structurally related PI3K inhibitors targeting the PI3K-d isoform for their ability to inhibit the survival of freshly isolated CLL cells. The purely PI3K-d-selective inhibitor idelalisib was compared to copanlisib and duvelisib (IPI-145), with isoform target profiles that additionally include PI3K-a or PI3K-c, respectively. The concentrations leading to half-maximal reduction of the survival of CLL cells were more than ten-fold lower for copanlisib than for idelalisib and duvelisib. At concentrations reflecting the biological availability of the different inhibitors, high levels of apoptotic response among CLL samples were attained more consistently with copanlisib than with idelalisib. Copanlisib selectively reduced the survival of CLL cells compared to T cells and to B cells from healthy donors. In addition copanlisib and duvelisib impaired the migration of CLL cells towards CXCL12 to a greater extent than equimolar idelalisib. Similarly copanlisib and duvelisib reduced the survival of CLL cells in co-cultures with the bone marrow stroma cell line HS-5 more strongly than idelalisib. Survival inhibition by copanlisib and idelalisib was enhanced by the monoclonal CD20 antibodies rituximab and obinutuzumab (GA101), while antibody-dependent cellular cytotoxicity mediated by alemtuzumab and peripheral blood mononuclear cells was not substantially impaired by both PI3K inhibitors for the CLL-derived JVM-3 cell line as target cells. Taken together, targeting the a-and d-p110 isoforms with copanlisib may be a useful strategy for the treatment of CLL and warrants further clinical investigation.Chronic lymphocytic leukemia (CLL) is a common B cell malignancy that usually occurs at advanced age and follows a highly variable course. 1 Although management of the disease has been steadily improved, with chemo-immunotherapy by fludarabine, cyclophosphamide and rituximab (FCR) as the current treatment standard for patients without co-morbidity, 2 there is a need for more efficient and less toxic therapies, since CLL can only be cured by allogeneic stem cell transplantation. Therefore, novel targeted agents are being developed, some of which show great promise and might replace chemotherapy regimens in the near future. 3

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 96%

Efficacy of phosphatidylinositol‐3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells

Göckeritz

Kerwien

Baumann

et al. 2015

Intl Journal of Cancer

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“…Studies have demonstrated that tumors with loss of the tumor suppressor PTEN , a PIP 3 phosphatase, display increased sensitivity to PI3Kβ and AKT inhibitors [13–15]. In contrast, cell lines with PIK3CA mutations generally do not respond to PI3Kβ inhibitors but encouraging results have been observed with PI3Kα and AKT inhibitors [16, 17]. …”

Section: Introductionmentioning

confidence: 99%

Identification of differential PI3K pathway target dependencies in T-cell acute lymphoblastic leukemia through a large cancer cell panel screen

et al. 2016

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Selective phosphoinositide 3-kinase (PI3K)/AKT/mTOR inhibitors are currently under evaluation in clinical studies. To identify tumor types that are sensitive to PI3K pathway inhibitors we screened compounds targeting PI3Kα/δ (AZD8835), PI3Kβ/δ (AZD8186), AKT (AZD5363) and mTORC1/2 (AZD2014) against a cancer cell line panel (971 cell lines). There was an enrichment of hematological malignancies that were sensitive to AKT and mTOR inhibition, with the greatest degree of sensitivity observed in T-cell acute lymphoblastic leukemia (T-ALL). We found that all NOTCH mutant T-ALL cell lines were sensitive to AKT and mTORC1/2 inhibitors, with only partial sensitivity to agents that target the PI3K α, β or δ isoforms. Induction of apoptosis only occurred following AKTi treatment in cell lines with PTEN protein loss and high levels of active AKT. In summary, we have demonstrated that T-ALL cell lines show differential sensitivity to inhibition at different nodes in the PI3K/AKT/mTOR pathway and inhibiting AKT or mTOR may have a therapeutic benefit in this disease setting.

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“…Mutations in BRAF were found to improve the response to broad acting drugs, though the clinical impact of the V600E mutation is not clear yet [39, 40]. In addition, oncogenic activation of the PI3K/AKT pathway can only partially be explained by previous investigations [11, 41, 42] and thus might also be explained by the occurrence of mutations in upstream molecules such as RTKs or other growth factors.…”

Section: Discussionmentioning

confidence: 99%

Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma

et al. 2016

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Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the “Deutsche Studiengruppe Multiples Myelom”. Subsequently, we correlated the detected mutations with common cytogenetic alterations and clinical parameters. We identified 11 novel non-synonymous SNVs or rare patient-specific SNPs, not listed in the SNP databases 1000 genomes and dbSNP, in 10 primary MM cases. The mutations predominantly affected the tyrosine-kinase and ligand-binding domains and no correlation with cytogenetic parameters was found. Interestingly, however, patients with RTK-mutations, specifically those with rare patient-specific SNPs, showed a significantly lower overall, event-free and progression-free survival. This indicates that RTK SNVs and rare patient-specific RTK SNPs are of prognostic relevance and suggests that MM patients with RTK-mutations could potentially profit from treatment with RTK-inhibitors.

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PI3K‐dependent multiple myeloma cell survival is mediated by the PIK3CA isoform

Cited by 19 publications

References 57 publications

Efficacy of phosphatidylinositol‐3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells

Efficacy of phosphatidylinositol‐3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells

Identification of differential PI3K pathway target dependencies in T-cell acute lymphoblastic leukemia through a large cancer cell panel screen

Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma

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