A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal

Mastri, Michalis; Tracz, Amanda; Lee, Christina R.; Dolan, Melissa; Attwood, Kristopher; Christensen, James G.; Liu, Song; Ebos, John M.L.

doi:10.1016/j.celrep.2018.12.017

Cited by 24 publications

(42 citation statements)

References 82 publications

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“…However, initial responders to therapy will eventually develop resistance to TKIs within 10-14 months [3,9]. The consequence of treatment failure in patients is deleterious due to the development of senescent phenotypes that contribute to tumor progression on therapy withdrawal [10]. Moreover, designing treatment strategies to overcome TKI resistance is challenging due to the lack of mechanistic insights and the availability of targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

Y-box binding protein-1 is crucial in acquired drug resistance development in metastatic clear-cell renal cell carcinoma

D’Costa

Lowerison

Raven

et al. 2020

J Exp Clin Cancer Res

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Background: Renal cell carcinoma (RCC) is a highly vascular tumor and patients with low risk metastatic RCC of clear-cell histological sub-type (mccRCC) are treated with tyrosine-kinase inhibitors (TKIs), sunitinib, as the first-line of treatment. Unfortunately, TKI resistance eventually develops, and the underlying molecular mechanism is not well understood. Methods: RCC cell-line with metastatic clear-cell histology (Caki-1), and patient samples were analysed to identify the role of Y-box binding protein 1 (YB-1) and ATP-binding cassette sub-family B member 1 (ABCB-1) in acquired sunitinib-resistance development. Caki-1 was conditioned with increasing sunitinib doses to recapitulate acquired resistance development in clinics. Sunitinib-conditioned and wild-type Caki-1 were subjected to cell viability assay, scratch assay, chicken embryo chorioallantoic membrane engraftment and proteomics analysis. Classical biochemical assays like flow cytometry, immunofluorescent staining, immunohistochemical staining, optical coherence tomography imaging, Western Blot and RT-PCR assays were applied to determine the possible mechanism of sunitinib-resistance development and the effect of drug treatments. Publicly available data was also used to determine the role of YB-1 upregulation in ccRCC and the patients' overall survival. Results: We demonstrate that YB-1 and ABCB-1 are upregulated in sunitinib-resistant in vitro, ex vivo, in vivo and patient samples compared to the sensitive samples. This provides evidence to a mechanism of acquired sunitinibresistance development in mccRCC. Furthermore, our results establish that inhibiting ABCB-1 with elacridar, in addition to sunitinib, has a positive impact on reverting sunitinib-resistance development in in vitro, ex vivo and in vivo models. Conclusion: This work proposes a targeted therapy (elacridar and sunitinib) to re-sensitize sunitinib-resistant mccRCC and, possibly, slow disease progression.

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Section: Introductionmentioning

confidence: 99%

Y-box binding protein-1 is crucial in acquired drug resistance development in metastatic clear-cell renal cell carcinoma

D’Costa

Lowerison

Raven

et al. 2020

J Exp Clin Cancer Res

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“…Cells with a senescence-associated secretory phenotype (SASP) secrete a special set of molecules that promotes the emergence of drug resistance in chemonaïve recipient tumor cells. This phenomenon has been demonstrated in senescent malignant pleural mesothelioma, melanoma, and breast cancer cells [207][208][209][210][211].…”

Section: From Cancer Cells To Cancer Cellsmentioning

confidence: 79%

New Insights into Therapy-Induced Progression of Cancer

Shnaider

Ivanova

Malyants

et al. 2020

IJMS

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The malignant tumor is a complex heterogeneous set of cells functioning in a no less heterogeneous microenvironment. Like any dynamic system, cancerous tumors evolve and undergo changes in response to external influences, including therapy. Initially, most tumors are susceptible to treatment. However, remaining cancer cells may rapidly reestablish the tumor after a temporary remission. These new populations of malignant cells usually have increased resistance not only to the first-line agent, but also to the second- and third-line drugs, leading to a significant decrease in patient survival. Multiple studies describe the mechanism of acquired therapy resistance. In past decades, it became clear that, in addition to the simple selection of pre-existing resistant clones, therapy induces a highly complicated and tightly regulated molecular response that allows tumors to adapt to current and even subsequent therapeutic interventions. This review summarizes mechanisms of acquired resistance, such as secondary genetic alterations, impaired function of drug transporters, and autophagy. Moreover, we describe less obvious molecular aspects of therapy resistance in cancers, including epithelial-to-mesenchymal transition, cell cycle alterations, and the role of intercellular communication. Understanding these molecular mechanisms will be beneficial in finding novel therapeutic approaches for cancer therapy.

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“…9 In our studies, we evaluated senescence markers and tumor growth after resistance to clinically approved VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs), and again after treatment had been stopped for short-term (24-48 hrs) or long-term (2-6 months) periods. 5 We found that VEGFR TKI-resistant mouse and human tumor cells originating from kidney carcinoma, breast carcinoma, or melanoma, progressed much more rapidly than controls when implanted orthotopically into mice when treatment was halted (representing short-term withdrawal conditions). Interestingly, these withdrawal-mediated tumor growth rebounds were found to diminish following long-term periods of drug removal, suggesting that tumor-promoting phenotypes were reversible for most cells.…”

mentioning

confidence: 90%

“…4 In a paper recently published in Cell Reports, we undertook a series of studies to investigate the role of senescence in promoting tumor growth after antiangiogenic therapy. 5 This was done for three reasons. First, angiogenesis inhibitors have been reported to promote metastasis in certain preclinical settings.…”

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confidence: 99%

Tumor growth fueled by spurious senescence phenotypes

Mastri

Ebos

2019

Molecular & Cellular Oncology

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A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal

Abstract: Highlights d Stopping antiangiogenic treatment after resistance leads to rebound tumor growth d Antiangiogenic drug resistance can induce transient pseudosenescent secretory phenotypes d Targeting SASP regulators like IL-6 and mTOR blunt withdrawal-mediated tumor growth

Cited by 24 publications

References 82 publications

Y-box binding protein-1 is crucial in acquired drug resistance development in metastatic clear-cell renal cell carcinoma

Y-box binding protein-1 is crucial in acquired drug resistance development in metastatic clear-cell renal cell carcinoma

New Insights into Therapy-Induced Progression of Cancer

Tumor growth fueled by spurious senescence phenotypes

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