Mechanisms of Drug Resistance Related to the Microenvironment of Solid Tumors and Possible Strategies to Inhibit Them

Tan, Qian; Saggar, Jasdeep K.; Yu, Man; Wang, Marina; Tannock, Ian F.

doi:10.1097/ppo.0000000000000131

Cited by 56 publications

(37 citation statements)

References 61 publications

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“…As a key feature in solid tumors, hypoxia is a contributor to the development of therapy resistance (15,20). The main challenge in TKI targeted therapy, including EGFR TKIs, is the development of resistance in tumors.…”

Section: Resultsmentioning

confidence: 99%

“…Tumor hypoxia is an important mediator of resistance to cancer therapy through multiple mechanisms (13,15,47). Tumor hypoxia also has significant effects on epigenetic regulation.…”

Section: Discussionmentioning

confidence: 99%

“…The negative impact of hypoxia on the efficacy of radio- and chemotherapy is well established (13,15,16). Hypoxia affects drug delivery, DNA repair, upregulation of resistance genes, and alters cell cycle and cell death pathways (13,17).…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1

Lü

Liu

Oeck

et al. 2018

Molecular Cancer Research

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The development of small-molecule tyrosine kinase inhibitors (TKIs) specific for epidermal growth factor receptors (EGFRs) with activating mutations has led to a new paradigm in the treatment of non-small cell lung cancer (NSCLC) patients. However, most patients eventually develop resistance. Hypoxia is a key micro-environmental stress in solid tumors that is associated with poor prognosis due, in part, to acquired resistance to conventional therapy. This study, documents that long-term, moderate hypoxia promotes resistance to the EGFR TKI, gefitinib, in the NSCLC cell line, HCC827, which harbors an activating EGFR mutation. Following hypoxic growth conditions, HCC827 cells treated with gefitinib upregulated N- cadherin, Fibronectin and Vimentin expression and downregulated E-cadherin, characteristic of an epithelial-mesenchymal transition (EMT) which prior studies have linked to EGFR TKI resistance. Mechanistically, knockdown of the histone demethylases, LSD1 and PLU-1, prevented and reversed hypoxia-induced gefitinib resistance, with inhibition of the associated EMT, suggesting that LSD1 and PLU-1 play key roles in hypoxia-induced gefitinib resistance and EMT. Moreover, hypoxia-treated HCC827 cells demonstrated more aggressive tumor growth in vivo compared to cells grown in normoxia, but inhibition of LSD1 function by shRNA- mediated knockdown or by the small-molecular inhibitor, SP2509, suppressed tumor growth and enhanced gefitinib response in vivo. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through epigenetic change and coordination of EMT in NSCLC. This study suggests that combination of therapy with EGFR TKIs and LSD1 inhibitors may offer an attractive therapeutic strategy for NSCLCs.

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Section: Resultsmentioning

confidence: 99%

“…Tumor hypoxia is an important mediator of resistance to cancer therapy through multiple mechanisms (13,15,47). Tumor hypoxia also has significant effects on epigenetic regulation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1

Lü

Liu

Oeck

et al. 2018

Molecular Cancer Research

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“…Tumours have convoluted vasculature which results in proliferating well-nourished cells closer to the functional blood vessels and regions of hypoxic cells located away from the functional blood vessels. Irregular blood flow and large distances between functional blood vessels in solid tumours lead to poor drug distribution, resulting in therapeutic resistance [60]. …”

Section: Methodsmentioning

confidence: 99%

Molecular mechanisms of hypoxia in cancer

Challapalli¹,

Carroll

Aboagye

2017

Clin Transl Imaging

127

108

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PurposeHypoxia is a condition of insufficient oxygen to support metabolism which occurs when the vascular supply is interrupted, or when a tumour outgrows its vascular supply. It is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. This review provides an overview of hypoxia imaging with Positron emission tomography (PET), with an emphasis on the biological relevance, mechanism of action, highlighting advantages, and limitations of the currently available hypoxia radiotracers.MethodsA comprehensive PubMed literature search was performed, identifying articles relating to biological significance and measurement of hypoxia, MRI methods, and PET imaging of hypoxia in preclinical and clinical settings, up to December 2016.ResultsA variety of approaches have been explored over the years for detecting and monitoring changes in tumour hypoxia, including regional measurements with oxygen electrodes placed under CT guidance, MRI methods that measure either oxygenation or lactate production consequent to hypoxia, different nuclear medicine approaches that utilise imaging agents the accumulation of which is inversely related to oxygen tension, and optical methods. The advantages and disadvantages of these approaches are reviewed, along with individual strategies for validating different imaging methods. PET is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels.ConclusionEven though hypoxia could have significant prognostic and predictive value in the clinic, the best method for hypoxia assessment has in our opinion not been realised.

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“…One of the potential mechanism of resistance to ADCs, as happens with antibodies, is associated with the limited drug distribution within the tumor due to their high molecular weight or tumor vascularization [100]. Similarly, elimination of chemotherapy from the intracellular compartment to the extracellular matrix could be another mechanism of resistance [101].…”

Section: Optimizing Combinatorial Strategiesmentioning

confidence: 99%

Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies

Ocaña

Pandiella

2017

Oncotarget

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Triple negative breast cancer (TNBC) is still an incurable disease despite the great scientific effort performed during the last years. The huge heterogeneity of this disease has motivated the evaluation of a great number of therapies against different molecular alterations. In this article, we review the biological bases of this entity and how the known molecular evidence supports the current preclinical and clinical development of new therapies. Special attention will be given to ongoing clinical studies and potential options for future drug combinations.

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Mechanisms of Drug Resistance Related to the Microenvironment of Solid Tumors and Possible Strategies to Inhibit Them

Cited by 56 publications

References 61 publications

Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1

Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1

Molecular mechanisms of hypoxia in cancer

Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies

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