The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways

Rahmani, Mohamed; Anderson, Anh; Habibi, Joseph; Crabtree, Timothy Ryan; Mayo, Mandy; Harada, Hisashi; Ferreira‐Gonzalez, Andrea; Dent, Paul; Grant, Steven

doi:10.1182/blood-2008-09-177881

Cited by 76 publications

(65 citation statements)

References 54 publications

(69 reference statements)

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“…Combined inhibition of both signaling pathways led to improved efficacy because of the enhanced induction of apoptosis, which can be in part attributed to the combined activation of pro-apoptotic BH3-only protein Bim as a result of MEK inhibition and repression of Mcl-1 as a result of PI3K/mTOR inhibition (35,39). Here, the ability of high Bim and low Mcl-1 expression to cooperatively initiate apoptosis in response to PI3K pathway and MEK inhibition is consistent with similar observations in human leukemia cells (40) and human lung cancer cell lines (41). In addition to exploring the effects of combining 2 targeted therapies, it is advantageous to exploit preclinical models to understand the effect of standard chemotherapies in combination with targeted therapeutics, given the established role of standard chemotherapy in ovarian cancer.…”

Section: Discussionsupporting

confidence: 75%

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

Kinross

Brown

Kleinschmidt

et al. 2011

Molecular Cancer Therapeutics

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The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is commonly dysregulated in human cancer, making it an attractive target for novel anticancer therapeutics. We have used a mouse model of ovarian cancer generated by Kras G12D activation and Pten deletion in the ovarian surface epithelium for the preclinical assessment of a novel PI3K/mTOR inhibitor PF-04691502. To enable higher throughput studies, we developed an orthotopic primary transplant model from these mice and evaluated therapeutic response to PF-04691502 using small-animal ultrasound and FDG-PET imaging. PF-04691502 inhibited tumor growth at 7 days by 72% AE 9. FDG-PET imaging revealed that PF-04691502 reduced glucose metabolism dramatically, suggesting FDG-PET may be exploited as an imaging biomarker of target inhibition by PF-04691502. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), were also dramatically inhibited following PF-04691502 treatment. However, as a single agent, PF-04691502 did not induce tumor regression and the long-term efficacy was limited, with tumor proliferation continuing in the presence of drug treatment. We hypothesized that tumor progression was because of concomitant activation of the mitogenactivated protein kinase pathway downstream of Kras G12D expression promoting cell survival and that the therapeutic effect of PF-04691502 would be enhanced by combinatory inhibition of MEK using PD-0325901. This combination induced striking tumor regression, apoptosis associated with upregulation of Bim and downregulation of Mcl-1, and greatly improved duration of survival. These data suggest that contemporaneous MEK inhibition enhances the cytotoxicity associated with abrogation of PI3K/mTOR signaling, converting tumor growth inhibition to tumor regression in a mouse model of ovarian cancer driven by PTEN loss and mutant K-Ras.

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Section: Discussionsupporting

confidence: 75%

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

Kinross

Brown

Kleinschmidt

et al. 2011

Molecular Cancer Therapeutics

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“…combination with PI3K/AKT/mTOR agents, that Bim, along with other BH3 proteins, mediates the observed apoptotic response (43,52,53). Therefore the observations in our studies suggest that Bim may be contributing to the apoptotic response.…”

Section: Tc-305 (Krasmentioning

confidence: 48%

“…The induction of apoptosis when the MAPK and PI3K/AKT/ mTOR pathways are both inhibited has been frequently observed across a number of genetic subtypes (21,43,51). Furthermore, a number of in vitro studies have shown that increases in the proapoptotic protein Bim is observed following combination therapy (26,52). In our studies we wanted to evaluate this mechanistic observation in our in vivo models.…”

Section: Tc-305 (Krasmentioning

confidence: 99%

Enhanced Apoptosis and Tumor Growth Suppression Elicited by Combination of MEK (Selumetinib) and mTOR Kinase Inhibitors (AZD8055)

et al. 2012

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The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal-regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non-small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy. Cancer Res; 72(7);

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“…Furthermore, we showed that the combination of a PI3K inhibitor and a MEK inhibitor could function, at least in part, through a combinatorial effect on MTOR signaling, as has been demonstrated in other cell types (46). Other potential mechanisms could also explain the effectiveness of this powerful combination, including overlapping effects on the apoptosis machinery (51). The limitation for this combination approach in the clinic has been increased toxicity (52,53).…”

Section: Discussionmentioning

confidence: 99%

Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110α

Gritsman¹,

Yuzugullu²,

Von³

et al. 2014

J. Clin. Invest.

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The genes encoding RAS family members are frequently mutated in juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemia (AML). RAS proteins are difficult to target pharmacologically; therefore, targeting the downstream PI3K and RAF/MEK/ERK pathways represents a promising approach to treat RAS-addicted tumors. The p110α isoform of PI3K (encoded by Pik3ca) is an essential effector of oncogenic KRAS in murine lung tumors, but it is unknown whether p110α contributes to leukemia. To specifically examine the role of p110α in murine hematopoiesis and in leukemia, we conditionally deleted p110α in HSCs using the Cre-loxP system. Postnatal deletion of p110α resulted in mild anemia without affecting HSC self-renewal; however, deletion of p110α in mice with KRAS G12D -associated JMML markedly delayed their death. Furthermore, the p110α-selective inhibitor BYL719 inhibited growth factor-independent KRAS G12D BM colony formation and sensitized cells to a low dose of the MEK inhibitor MEK162. Furthermore, combined inhibition of p110α and MEK effectively reduced proliferation of RAS-mutated AML cell lines and disease in an AML murine xenograft model. Together, our data indicate that RAS-mutated myeloid leukemias are dependent on the PI3K isoform p110α, and combined pharmacologic inhibition of p110α and MEK could be an effective therapeutic strategy for JMML and AML.

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The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways

Cited by 76 publications

References 54 publications

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

Enhanced Apoptosis and Tumor Growth Suppression Elicited by Combination of MEK (Selumetinib) and mTOR Kinase Inhibitors (AZD8055)

Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110α

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