Dual modulation of MCL-1 and mTOR determines the response to sunitinib

Elgendy, Mohamed; Abdel-Aziz, Amal Kamal; Renne, Salvatore Lorenzo; Bornaghi, Viviana; Procopio, Giuseppe; Colecchia, Maurizio; Kanesvaran, Ravindran; Toh, Chee-Keong; Bossi, Daniela; Pallavicini, Isabella; Perez-Gracia, José Luis; Lozano, Marı́a D.; Giandomenico, Valeria; Mercurio, Ciro; Lanfrancone, Luisa; Fazio, Nicola; Nolè, Franco; Teh, Bin Tean; Renne, Giuseppe; Minucci, Saverio

doi:10.1172/jci84386

Cited by 52 publications

(55 citation statements)

References 52 publications

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“…Next, we aimed to gain deeper insight into the mechanisms by which the identified proteins mediate the antitumor effects of sunitinib. We recently reported that modulation of the prosurvival MCL‐1 protein and mTORC1 signaling downstream of the ERK and GSK3β pathways plays a crucial role in determining the response to sunitinib . Consistently, we observed that treatment of sunitinib‐sensitive RCC A‐498 cells with cytotoxic doses of sunitinib was associated with time‐dependent reduction in MCL‐1 levels and inhibition of mTORC1 activity as assessed by the phosphorylation of downstream targets (Fig.…”

Section: Resultssupporting

confidence: 81%

“…Furthermore, we investigated whether there is a link between the identified resistance‐associated proteins and the mechanisms that we recently showed to determine the response and intrinsic resistance to sunitinib, namely modulation of MCL‐1 level and of mTORC1 signaling through modulating upstream GSK3β and ERK signaling . Induction of MCL‐1 and mTORC1 acts as prosurvival stress responses geared toward impeding sunitinib cytotoxicity and imparting cancer cells and tumors with resistance against sunitinib.…”

Section: Discussionmentioning

confidence: 99%

“…The authenticity of those cell lines has been proven by DNA profiling using GenePrint 10 Promega kit. Sunitinib‐desensitized paired cell lines were generated by continuous culturing in the presence of increasing doses of sunitinib as described as described elsewhere . All cells were grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum and 2 mM l ‐glutamine unless otherwise indicated.…”

Section: Methodsmentioning

confidence: 99%

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Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

Elgendy

Fusco

Segura

et al. 2019

Intl Journal of Cancer

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Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor‐suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib‐desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low‐dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.

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Section: Resultssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

Elgendy

Fusco

Segura

et al. 2019

Intl Journal of Cancer

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“…In our study published recently, 4 we applied a unique approach as compared with other studies, focusing on the adaptive pro-survival responses that cells opt to for maintaining their viability and tolerating the cytotoxic effects triggered by sunitinib. We then further analyzed the relevance of those adaptive responses to intrinsic as well as acquired resistance of cancer cells to sunitinib.…”

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confidence: 99%

The yin yang of sunitinib: One drug, two doses, and multiple outcomes

Elgendy

2017

Molecular & Cellular Oncology

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Our recent work showed that sunitinib exerts dual effect on cancer cells in different dose ranges. In clinically relevant doses, cancer cells tolerate sunitinb cytotoxicity by upregulating pro-survival MCL-1 and activating mTORC1 signaling. Inhibition of MCL-1 or mTORC1 sensitized cancer cells to sunitinib. Analysis of tissues from patients correlated MCL-1/mTORC1 induction with resistance to sunitinib.

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“…Our study fills this gap at least partially by providing a mechanism and through that a novel efficacious combination therapy, involving GW3965 and LXR623. Because Bcl-2 family members are central regulators of cell death in malignant tumors (Preuss et al, 2013;Souers et al, 2013;Chan et al, 2015;Faber et al, 2015;Hata et al, 2015;Johnson-Farley et al, 2015;Elgendy et al, 2016;Karpel-Massler et al, 2017c), we hypothesized that LXR agonists have an impact on their expression. While certain members of this family are more relevant in hematological malignancies, others maintain a pivotal role in solid tumors.…”

Section: Discussionmentioning

confidence: 99%

Activation of LXR β inhibits tumor respiration and is synthetically lethal with Bcl‐ xL inhibition

et al. 2019

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Liver‐X‐receptor (LXR) agonists are known to bear anti‐tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti‐proliferative effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U‐13C‐glucose and U‐13C‐glutamine) reveal that within 5 h, activation of LXRβ results in reprogramming of tumor cell metabolism, leading to suppression of mitochondrial respiration, a phenomenon not observed in normal human astrocytes. LXR activation elicits a suppression of respiratory complexes at the protein level by reducing their stability. In turn, energy starvation drives an integrated stress response (ISR) that up‐regulates pro‐apoptotic Noxa in an ATF4‐dependent manner. Cholesterol and nucleotides rescue from the ISR elicited by LXR agonists and from cell death induced by LXR agonists and BH3 mimetics. In conventional and patient‐derived xenograft models of colon carcinoma, melanoma, and glioblastoma, the combination treatment of ABT263 and LXR agonists reduces tumor sizes significantly stronger than single treatments. Therefore, the combination treatment of LXR agonists and BH3 mimetics might be a viable efficacious treatment approach for solid malignancies.

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Dual modulation of MCL-1 and mTOR determines the response to sunitinib

Cited by 52 publications

References 52 publications

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

The yin yang of sunitinib: One drug, two doses, and multiple outcomes

Activation of LXR β inhibits tumor respiration and is synthetically lethal with Bcl‐ xL inhibition

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