Kitlow Stem Cells Cause Resistance to Kit/Platelet-Derived Growth Factor α Inhibitors in Murine Gastrointestinal Stromal Tumors

Bardsley, Michael R.; Horváth, Viktor J.; Asuzu, David T.; Lörincz, Andrea; Redelman, Doug; Hayashi, Yujiro; Popko, Laura; Young, David; Lomberk, Gwen; Urrutia, Raúl; Farrugia, Gianrico; Rubin, Brian P.; Ördög, Tamás

doi:10.1053/j.gastro.2010.05.083

Cited by 110 publications

(177 citation statements)

References 29 publications

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“…Although the GR cells analyzed here were selected from cell lines in vitro, studies show that some EGFR-mutant lung cancers with acquired TKI resistance display an EMT phenotype in the clinic. [5][6][7][8] Like EGFR-mutant lung cancer, chronic myeloid leukemia, which has the Bcr-Abl fusion gene, 32 and gastrointestinal stromal tumors, which harbors an activating mutation in the c-kit gene, 33 are addicted to constitutively activated tyrosine kinases. Intriguingly, these In this study, we have also uncovered that GR cells have a higher degree of basal autophagy than their parental cells, which endows them with the potential to evade apoptosis and proliferate even under hypoxic conditions in vitro.…”

Section: Discussionmentioning

confidence: 99%

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Sakuma

Matsukuma

Nakamura

et al. 2013

Laboratory Investigation

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Lung cancers harboring epidermal growth factor receptor (EGFR) mutations depend on constitutive activation of the kinase for survival. Although most EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs) and shrink in response to treatment, acquired resistance to TKI therapy is common. We demonstrate here that two EGFRmutated lung adenocarcinoma cell lines, HCC827 and HCC4006, contain a subpopulation of cells that have undergone epithelial-to-mesenchymal transition and survive independent of activated EGFR. These EGFR-independent cancer cells, herein termed gefitinib-resistant (GR) cells, demonstrate higher levels of basal autophagy than their parental cells and thrive under hypoxic, reduced-serum conditions in vitro; this somewhat simulates the hypoxic environment common to cancerous tissues. We show that depletion of the essential autophagy gene, ATG5, by small interfering RNA (siRNA) or chloroquine, an autophagy inhibitor, markedly reduces GR cell viability under hypoxic conditions. Moreover, we show a significant elevation in caspase activity in GR cells following knockdown of ATG5. These results suggest that GR cells can evade apoptosis and survive in hostile, hypoxic environments with constant autophagic flux. We also show the presence of autophagosomes in some cancer cells from patient samples, even in untreated EGFR-mutant lung cancer tissue samples. Together, our results indicate that autophagy inhibitors alone or in combination with EGFR TKIs may be an effective approach for the treatment of EGFR-mutant lung cancers, where basal autophagy of some cancer cells is upregulated.

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Section: Discussionmentioning

confidence: 99%

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Sakuma

Matsukuma

Nakamura

et al. 2013

Laboratory Investigation

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“…In particular, it targets CD44 + CD24 -cells in breast carcinoma 7 as well as c-kit low CD44 + CD34 + cells with imatinib resistance in a genetic mouse model of gastrointestinal stromal tumors. 17 In principle, its efficacy against any given subpopulation may arise not only from direct toxicity to that phenotype, but by altering the dynamic interconversion between epithelial and mesenchymal-like subpopulations. For instance, salinomycin's depletion …”

Section: Discussionmentioning

confidence: 99%

Detecting and targeting mesenchymal-like subpopulations within squamous cell carcinomas

et al. 2011

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“…Based on the intertwined relationship between EMT processes and cancer stem cells, direct targeting of the latter may also manage the diseaserelated aspects of EMT in cancer. As an example, a promising CSC-targeting drug, salinomycin, was isolated by Gupta et al form a library of 16,000 small molecules (59) and has yielded interesting preclinical results in several tumor entities (60)(61)(62)(63)(64).…”

Section: Emt In Cancermentioning

confidence: 99%

Epigenetic control of epithelial-mesenchymal-transition in human cancer

Kiesslich

Pichler

Neureiter

2012

Molecular and Clinical Oncology

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Abstract. Development and tissue homeostasis as well as carcinogenesis share the evolutionary conserved process of epithelial-mesenchymal transition (EMT). EMT enables differentiated epithelial cells to trans-differentiate to a mesenchymal phenotype which is associated with diverse cellular properties including altered morphology, migration and invasion and stemness. In physiological development and tissue homeostasis, EMT exerts beneficial functions for structured tissue formation and maintenance. Under pathological conditions, EMT causes uncontrolled tissue repair and organ fibrosis, as well as the induction of tumor growth, angiogenesis and metastasis in the context of cancer progression. Particularly, the metastatic process is essentially linked to diverse EMT-driven functions which give the mesenchymal differentiated tumor cells the capacity to migrate and form micrometastases in distant organs. Recent analyses of the mechanisms controlling EMT revealed a significant epigenetic regulatory impact reflecting the reversible nature of EMTs. As several approaches of epigenetic therapy are already under clinical evaluation, including inhibitors of DNA methyl transferase and histone deacetylase, targeting the epigenetic regulation of EMT may represent a promising therapeutic option in the future. Therefore, we undertook this review to reassess the current knowledge on the roles of epigenetic control in the regulation of EMT in human cancer. These recent findings are discussed in view of their implications on future diagnostic and therapeutic strategies.

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Kitlow Stem Cells Cause Resistance to Kit/Platelet-Derived Growth Factor α Inhibitors in Murine Gastrointestinal Stromal Tumors

Cited by 110 publications

References 29 publications

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Detecting and targeting mesenchymal-like subpopulations within squamous cell carcinomas

Epigenetic control of epithelial-mesenchymal-transition in human cancer

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