Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives

Joosten, Sophie C.; Hamming, Lisanne C.; Soetekouw, Patricia M.M.B.; Aarts, Maureen J.B.; Veeck, Jürgen; Engeland, Manon van; Tjan-Heijnen, Vcg

doi:10.1016/j.bbcan.2014.11.002

Cited by 73 publications

(83 citation statements)

References 167 publications

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“…5,38 However, this therapeutic strategy is rarely curative, as RCC usually develops resistance to the tyrosine kinase inhibitors. 7,8,11,45 Broader inhibition of the angiogenic pathways, as was investigated in this study, might therefore result in a more durable clinical response. Two possible methods of achieving such a response include (i) the use of an inhibitor that affects multiple signaling cascades simultaneously or (ii) targeting a common upstream element of these pathways; in the case of RCC, many of these pathways share the transcriptional activator, HIF- α .…”

Section: Discussionmentioning

confidence: 93%

“…5 For metastatic RCC in particular, the two standard targets are the VEGF receptor and mammalian target of rapamycin (mTOR), a downstream component in the phosphoinositide 3-kinase (PI3K)/AKT pathway known to upregulate HIF-1α activity. 6 Unfortunately, tumors frequently develop resistance to these targeted therapies by activating bypass pathways in response to VEGF 7,8 or mTOR inhibition. 9 …”

Section: Introductionmentioning

confidence: 99%

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Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

Chen

Fong

et al. 2017

Oncogene

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Targeted therapeutics, such as those abrogating hypoxia inducible factor (HIF)/vascular endothelial growth factor signaling, are initially effective against kidney cancer (or renal cell carcinoma, RCC); however, drug resistance frequently occurs via subsequent activation of alternative pathways. Through genome-scale integrated analysis of the HIF-α network, we identified the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) as a potential target molecule for kidney cancer. In a screen of nephrectomy samples from 56 patients with RCC, we found that MARCKS expression and its phosphorylation are increased and positively correlate with tumor grade. Genetic and pharmacologic suppression of MARCKS in high-grade RCC cell lines in vitro led to a decrease in cell proliferation and migration. We further demonstrated that higher MARCKS expression promotes growth and angiogenesis in vivo in an RCC xenograft tumor. MARCKS acted upstream of the AKT/mTOR pathway, activating HIF-target genes, notably vascular endothelial growth factor-A. Following knockdown of MARCKS in RCC cells, the IC50 of the multikinase inhibitor regorafenib was reduced. Surprisingly, attenuation of MARCKS using the MPS peptide synergistically interacted with regorafenib treatment and decreased survival of kidney cancer cells through inactivation of AKT and mTOR. Our data suggest a major contribution of MARCKS to kidney cancer growth and provide an alternative therapeutic strategy of improving the efficacy of multikinase inhibitors.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

Chen

Fong

et al. 2017

Oncogene

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“…All patients eventually progressed on therapy, and this indicated some form of acquired resistance after exposure to sunitinib. Resistance to sunitinib has been best elucidated in patients with renal cell carcinoma, where it has been found to be related to upregulation of proangiogenic and other alternate signaling pathways, changes in the tumor microenvironment, and the action of microRNAs …”

Section: Discussionmentioning

confidence: 99%

Phase 2 study of sunitinib in patients with metastatic mucosal or acral melanoma

Buchbinder

Sosman

Lawrence

et al. 2015

Cancer

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BACKGROUND:Patients with mucosal and acral melanomas have limited treatment options and a poor prognosis. Mutations of the KIT oncogene in these melanoma subtypes provide a potential therapeutic target. METHODS: A multicenter phase 2 trial of sunitinib was conducted in patients with unresectable stage III or IV melanoma of a mucosal or acral primary origin. Patients were treated in 2 cohorts: cohort A received sunitinib at a dose of 50 mg daily for 4 weeks of a 6-week cycle, and cohort B received sunitinib at a dose of 37.5 mg daily on a continuous basis. Dose reductions were permitted for treatment-related toxicities, and tumor assessments were performed every 2 months. RESULTS: Fifty-two patients were enrolled: 21 in cohort A and 31 in cohort B. Four patients had confirmed partial responses, which lasted 5 to 10 months (1 with a KIT mutation). In both cohorts, the proportion of patients alive and progression-free at 2 months was 52% (95% confidence interval, 38%-66%); this was significantly larger than the hypothesized null of 5%. There was no significant difference in response or overall survival between the 25% of patients with a KIT mutation and those without one (response rate, 7.7% vs 9.7%; overall survival, 6.4 vs 8.6 months). The overall disease control rate was 44%, and a high rate of toxicity was associated with the treatment. CONCLUSIONS: Sunitinib showed activity in the treatment of mucosal and acral melanoma that was not dependent on the presence of a KIT mutation. However, the medication was poorly tolerated, and there were no prolonged responses. Cancer 2015;121:4007-15.

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“…Understanding the molecular mechanism underlying intrinsic and acquired resistance to sunitinib may provide clues on how to circumvent this clinical problem. Several sunitinib resistance mechanisms, such as the upregulation of proangiogenic signaling pathways, increased tumor invasiveness and metastasis, activation of alternative signaling pathways, inadequate target inhibition, and resistance mediated by the tumor microenvironment or by the action of microRNAs, have been reported [for an extensive review, see the article by Joosten et al (15)]. The evidence of most of these mechanisms has been derived from preclinical models, and their clinical relevance needs to be proven.…”

Section: Resistance Mechanismsmentioning

confidence: 99%

The Potential Role of Lysosomal Sequestration in Sunitinib Resistance of Renal Cell Cancer

Azijli

Gotink

Verheul

2016

jkcvhl

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Renal cell carcinoma (RCC) is a highly vascularized tumor type, which is often associated with inactivated mutations in the von Hippel-Lindau gene that drives proangiogenic signaling pathways. As such, new therapies for the treatment of RCC have largely been focused on blocking angiogenesis. Sunitinib, an antiangiogenic tyrosine kinase inhibitor, is the most frequently used first-line drug for the treatment of RCC. Although treatment with sunitinib improves patient outcome considerably, acquired resistance will emerge in all cases. The molecular mechanisms of resistance to sunitinib are poorly understood, but in the past decade, several of these have been proposed. Lysosomal sequestration of sunitinib was reported as a potential resistance mechanism to sunitinib. In this review, the underlying molecular mechanisms of lysosomal sunitinib sequestration and the potential strategies to overcome this resistance are discussed to be able to further improve the treatment of RCC.

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Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives

Cited by 73 publications

References 167 publications

Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

Phase 2 study of sunitinib in patients with metastatic mucosal or acral melanoma

The Potential Role of Lysosomal Sequestration in Sunitinib Resistance of Renal Cell Cancer

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