Dual inhibition of mTOR pathway and VEGF signalling in neuroendocrine neoplasms: From bench to bedside

Cella, Chiara Alessandra; Minucci, Saverio; Spada, Francesca; Galdy, Salvatore; Elgendy, Mohamed; Ravenda, Paola Simona; Zampino, Maria Giulia; Murgioni, Sabina; Fazio, Nicola

doi:10.1016/j.ctrv.2015.06.008

Cited by 21 publications

(13 citation statements)

References 75 publications

(74 reference statements)

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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%

“…27,28 mTORC1 signaling is another crucial factor in determining the response to anticancer agents and is implicated in diverse cellular processes including regulation of cellular energetics, autophagy, survival and proliferation. 11,29 Our results showed that loss-of-function of the identified resistance-associated proteins in cells desensitized to sunitinib either by continuous exposure to increasing doses or by depletion of the identified six proteins impeded sunitinib-evoked modulation of these oncogenic pathways. These findings link mechanisms of intrinsic and acquired resistance to sunitinib and indicate that reactivation of mechanisms of intrinsic resistance upon acquiring the identified mutations contributes to acquired resistance after a period of treatment with sunitinib.…”

Section: Discussionmentioning

confidence: 76%

“…However, emerging reports suggest that MCL‐1 is also implicated in other cellular processes that contribute to its tumorigenic potential . mTORC1 signaling is another crucial factor in determining the response to anticancer agents and is implicated in diverse cellular processes including regulation of cellular energetics, autophagy, survival and proliferation …”

Section: Discussionmentioning

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: 76%

Section: Discussionmentioning

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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“…Despite some success, relatively few sequential combinations have entered clinical practice, as until recently the molecular understanding of their efficacy has been lacking [79]. DNA and RNA sequencing technologies are now at a point where they can be used as companion diagnostic technologies, and the effects of sequential drug administration can be predicted [80].…”

Section: Strategies To Overcome Resistancementioning

confidence: 99%

Molecular chess? Hallmarks of anti-cancer drug resistance

2017

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BackgroundThe development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years.ReviewResistance to anti-cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as (1) alteration of drug targets, (2) expression of drug pumps, (3) expression of detoxification mechanisms, (4) reduced susceptibility to apoptosis, (5) increased ability to repair DNA damage, and (6) altered proliferation. It is clear, however, that changes in stroma and tumour microenvironment, and local immunity can also contribute to the development of resistance. Cancer cells can and do use several of these mechanisms at one time, and there is considerable heterogeneity between tumours, necessitating an individualised approach to cancer treatment. As tumours are heterogeneous, positive selection of a drug-resistant population could help drive resistance, although acquired resistance cannot simply be viewed as overgrowth of a resistant cancer cell population. The development of such resistance mechanisms can be predicted from pre-existing genomic and proteomic profiles, and there are increasingly sophisticated methods to measure and then tackle these mechanisms in patients.ConclusionThe oncologist is now required to be at least one step ahead of the cancer, a process that can be likened to ‘molecular chess’. Thus, as well as an increasing role for predictive biomarkers to clinically stratify patients, it is becoming clear that personalised strategies are required to obtain best results.

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“…When the GAP activity of TSC2 is inhibited, Rheb accumulates in the GTP-bound state and ultimately leads to mTORC1 activation (28). Consistent with its multivalent cellular functions, the contribution of mTOR to tumorigenesis therefore occurs through multiple processes and its relevance is highlighted by the prominent role gained by drugs targeting mTOR in cancer therapy (31,32).…”

Section: Introductionmentioning

confidence: 99%