PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis

Ilić, Nina; Utermark, Tamara; Widlund, Hans R.; Roberts, Thomas M.

doi:10.1073/pnas.1108237108

Cited by 194 publications

(169 citation statements)

References 53 publications

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“…In the Eμ‐Myc mouse model, mTORC1 activation was shown to accelerate lymphomagenesis by inhibiting Myc‐induced apoptosis through translational upregulation of the anti‐apoptotic protein myeloid cell leukemia 1 (Mcl1; Mills et al , 2008), suggesting a collaboration of Myc and mTORC1 in tumor initiation. On the contrary, MYC amplification was shown to confer resistance to mTORC1 inhibition through transcriptional activation of the eukaryotic translation initiation factor 4E (eIF4E), suggesting that mTORC1 function is not critical in the context of high MYC expression (Ilic et al , 2011). Correspondingly, in a chemical screen study elevated MYC levels correlated with enhanced resistance to PI3K/mTORC1 inhibition (Muellner et al , 2011).…”

Section: Discussionmentioning

confidence: 99%

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

et al. 2018

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The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient‐sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC‐driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR‐15a. TSC1 knockdown results in elevated mTORC1‐dependent mitochondrial respiration enhanced ROS production and apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC‐driven cancers.

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Section: Discussionmentioning

confidence: 99%

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

et al. 2018

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“…For example, NVP-BEZ235 upregulates ER expression in ER-positive luminal B subtype of breast carcinomas (34). Long-term NVP-BEZ235 treatment also stimulates MYC expression and leads to drug resistance in breast cancers (25,26).…”

Section: Discussionmentioning

confidence: 99%

“…The transcription of MYC is promoted by AR in prostate cancers, whereas AR suppresses MYC expression in female breast carcinomas (23,24). Recent studies show that long-term NVP-BEZ235 treatment upregulates MYC expression in breast cancer cells, leading to NVP-BEZ235 resistance (25,26). Therefore, we postulated that the presence of DHT during NVP-BEZ235 treatment could effectively block NVP-BEZ235-induced MYC upregulation in breast cancers.…”

Section: Armentioning

confidence: 99%

Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

Wang

et al. 2014

Molecular Cancer Therapeutics

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NVP-BEZ235 is a newly developed dual PI3K/mTOR inhibitor, being tested in multiple clinical trials, including breast cancer. NVP-BEZ235 selectively induces cell growth inhibition in a subset, but not all, breast cancer cell lines. However, it remains a challenge to distinguish between sensitive and resistant tumors, particularly in the pretreatment setting. Here, we used ten breast cancer cell lines to compare NVP-BEZ235 sensitivity and in the context of androgen receptor (AR) activation during NVP-BEZ235 treatment. We also used female SCID mice bearing breast tumor xenografts to investigate the beneficial effect of dihydrotestosterone/NVP-BEZ235 combination treatment compared with each alone. We found that AR-positive breast cancer cell lines are much more sensitive to NVP-BEZ235 compared with AR-negative cells, regardless of PTEN or PI3KCA status. Reintroducing AR expression in NVP-BEZ235 nonresponsive AR-negative cells restored the response. DHT/NVP-BEZ235 combination not only resulted in a more significant growth inhibition than either drug alone, but also achieved tumor regression and complete responses for AR þ /ER þ tumors. This beneficial effect was mediated by dihydrotestosterone (DHT)-induced PTEN and KLLN expression. Furthermore, DHT could also reverse NVP-BEZ235-induced side effects such as skin rash and weight loss. Our data suggest that AR expression may be an independent predictive biomarker for response to NVP-BEZ235. AR induction could add benefit during NVP-BEZ235 treatment in patients, especially with AR þ

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“…In contrast, blocking eIF4F helicase activity was a more effective means of sensitizing JJN-3 cells to DEX. An advantage of using silvestrol over mTOR or PI3K/TOR KIs is that elevated eIF4E levels can lead to PI3K/TOR KI resistance (32), and by inhibiting eIF4A, one targets downstream of this resistance node.…”

Section: Discussionmentioning

confidence: 99%

Translation initiation factor eIF4F modifies the dexamethasone response in multiple myeloma

Robert¹,

Roman²,

Bramoullé

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Enhanced protein synthesis capacity is associated with increased tumor cell survival, proliferation, and resistance to chemotherapy. Cancers like multiple myeloma (MM), which display elevated activity in key translation regulatory nodes, such as the PI3K/ mammalian target of rapamycin and MYC-eukaryotic initiation factor (eIF) 4E pathways, are predicted to be particularly sensitive to therapeutic strategies that target this process. To identify novel vulnerabilities in MM, we undertook a focused RNAi screen in which components of the translation apparatus were targeted. Our screen was designed to identify synthetic lethal relationships between translation factors or regulators and dexamethasone (DEX), a corticosteroid used as frontline therapy in this disease. We find that suppression of all three subunits of the eIF4F cap-binding complex synergizes with DEX in MM to induce cell death. Using a suite of small molecules that target various activities of eIF4F, we observed that cell survival and DEX resistance are attenuated upon eIF4F inhibition in MM cell lines and primary human samples. Levels of MYC and myeloid cell leukemia 1, two known eIF4F-responsive transcripts and key survival factors in MM, were reduced upon eIF4F inhibition, and their independent suppression also synergized with DEX. Inhibition of eIF4F in MM exerts pleotropic effects unraveling a unique therapeutic opportunity.silvestrol | hippuristanol | eIF4A | RNAi screening

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PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis

Cited by 194 publications

References 53 publications

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

Translation initiation factor eIF4F modifies the dexamethasone response in multiple myeloma

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