Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epithelial-mesenchymal transition

Kogita, Akihiro; Togashi, Yosuke; Hayashi, Hidetoshi; Sogabe, Shunsuke; Terashima, Masato; Velasco, Marco A. De; Sakai, Kazuko; Fujita, Yoshihiko; Tomida, Shuta; Takeyama, Yoshifumi; Okuno, Kiyotaka; Nakagawa, Kazuhiko; Nishio, Kazuto

doi:10.3892/ijo.2014.2574

Cited by 52 publications

(51 citation statements)

References 35 publications

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“…Kim et al reported that long-term exposure to crizotinib induces EMT in cases of lung adenocarcinoma, causing crizotinib resistance (2). Furthermore, Kogita et al described that hypoxia induces resistance to ALK inhibitors via the EMT in NSCLC patients with ALK rearrangement (12). Based on these results, the findings in our case suggest the possibility of transformation into pleomorphic carcinoma as a result of the EMT in patients with lung cancer.…”

Section: Discussionsupporting

confidence: 60%

Anaplastic Lymphoma Kinase (ALK) Rearrangement-positive Lung Cancer with Transformation to Pleomorphic Carcinoma

et al. 2015

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A 55-year-old woman was diagnosed with a tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) rearrangement-positive lung adenocarcinoma and treated with chemotherapy consisting of crizotinib, a tyrosine kinase inhibitor of ALK, as second-line chemotherapy. However, the size of the metastatic adrenal lesion increased, and the patient died due to multiple organ failure. An autopsy report revealed that the metastatic lesion of the adrenal tumor was ALK rearrangement-positive pleomorphic carcinoma. The epithelialmesenchymal transition (EMT) marker vimentin was immunohistochemically positive in both the lung and adrenal lesions. The present case report suggests the possibility of transformation into pleomorphic carcinoma as a result of EMT in patients with ALK rearrangement-positive lung cancer.

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Section: Discussionsupporting

confidence: 60%

Anaplastic Lymphoma Kinase (ALK) Rearrangement-positive Lung Cancer with Transformation to Pleomorphic Carcinoma

et al. 2015

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“…These findings suggest that activation of MET signaling may serve as a salvage signal after alectinib treatment, which is possibly not observed in crizotinib-resistance due to the high inhibitory activity of crizotinib against MET [19,20]. As well as crizotinib-resistance, other groups have demonstrated that EGFR ligands and hypoxia-induced EMT confer resistance to alectinib [43,48]. The resistance mechanism via the bypass track has yet to be reported in ceritinib-resistant patients or cells, which should therefore be investigated in clinical and pre-clinical settings.…”

Section: Resistance Mechanisms To Alk Inhibitorsmentioning

confidence: 99%

“…With regard to the involvement of alternate signaling pathways in the acquisition of resistance to next-generation ALK inhibitors, few reports exist thus far [43,47,48,49]. In particular, the involvement of hepatocyte growth factor (HGF)/MET signaling pathway activation in the acquired resistance to alectinib has been demonstrated by several groups [47,48,49].…”

Section: Resistance Mechanisms To Alk Inhibitorsmentioning

confidence: 99%

“…4 of 5 tumor samples taken at the time of acquired resistance to crizotinib displayed increased levels of pIGF-1R, which indicates activation of the IGF-1R pathway. Other possible resistance mechanisms identified by pre-clinical investigation include EGFR ligands, EMT, and autophagy, whose significance in clinical settings remains unclear [42,43,44]. In addition, Giri et al [46] identified novel mutations of 7 genes ( CSMD3 , CDKN2A , MAGI1 , CREBBP , DOT1L , PBX1 , and PRKDC ) in a crizotinib-resistant tumor sample; however, their role in the acquired resistance to crizotinib was unclear due to the lack of data before the administration of crizotinib and the lack of basic experiments.…”

Section: Resistance Mechanisms To Alk Inhibitorsmentioning

confidence: 99%

“…The data regarding resistance to crizotinib include EGFR mutation [40], KRAS mutation [40], activation of the ErbB family through phosphorylation [37], amplification of KIT [37], activation of the insulin-like growth factor 1 receptor (IGF-1R) pathway [41], EGFR ligands [42], hypoxia-induced epithelial-mesenchymal transition (EMT) [43], and autophagy [44]. …”

Section: Resistance Mechanisms To Alk Inhibitorsmentioning

confidence: 99%

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Updated Evidence on the Mechanisms of Resistance to ALK Inhibitors and Strategies to Overcome Such Resistance: Clinical and Preclinical Data

Toyokawa

Seto

2015

Oncol Res Treat

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Anaplastic lymphoma kinase(ALK) rearrangement is one of the oncogenes in non-small cell lung cancer (NSCLC) identified in 2007. The PROFILE trials demonstrated that patients with ALK-rearranged NSCLC can be successfully treated with crizotinib, and that crizotinib is superior to chemotherapy in both first- and second-line settings. Furthermore, next-generation ALK inhibitors, such as alectinib and ceritinib, have been shown to harbor excellent efficacy for NSCLC patients with ALK rearrangement. However, it is known that many cases ultimately acquire resistance to ALK inhibitors. Some potential mechanisms of resistance to ALK inhibitors are as follows: ALK dominant resistance, such as secondary mutations and copy number gain in the ALK gene; activation of the bypass tracks, including EGFR, KRAS, KIT, MET, and IGF-1R. Furthermore, treatment strategies to overcome these resistance mechanisms have been proposed, and next-generation ALK inhibitors, agents which inhibit the bypass tracks, and heat shock protein 90 inhibitors are thought to be promising. Thus, clinical and pre-clinical evidence on the resistance mechanisms to ALK inhibitors and treatment strategies to overcome the resistance have been gradually obtained. Herein, we concisely review the current clinical and pre-clinical data regarding the mechanisms of resistance to ALK inhibitors and treatments to overcome such resistance.

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EML4‐ALK biology and drug resistance in non‐small cell lung cancer: a new phase of discoveries

Elshatlawy,

Sampson,

Clarke

et al. 2023

Molecular Oncology

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Anaplastic lymphoma kinase (ALK) can be driven to oncogenic activity by different types of mutational events such as point-mutations, for example F1174L in neuroblastoma, and gene fusions, for example with echinoderm microtubule-associated protein-like 4 (EML4) in non-small cell lung cancer (NSCLC). EML4-ALK variants result from different breakpoints, generating fusions of different sizes and properties. The most common variants (Variant 1 and Variant 3) form cellular compartments with distinct physical properties. The presence of a partial, probably misfolded beta-propeller domain in variant 1 confers solid-like properties to the compartments it forms, greater dependence on Hsp90 for protein stability and higher cell sensitivity to ALK tyrosine kinase inhibitors (TKIs). These differences translate to the clinic because variant 3, on average, worsens patient prognosis and increases metastatic risk. Latest generation ALK-TKIs are beneficial for most patients with EML4-ALK fusions. However, resistance to ALK inhibitors can occur via point-mutations within the kinase domain of the EML4-ALK fusion, for example G1202R, reducing inhibitor effectiveness. Here, we discuss the biology of EML4-ALK variants, their impact on treatment response, ALK-TKI drug resistance mechanisms and potential combination therapies.

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Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epithelial-mesenchymal transition

Cited by 52 publications

References 35 publications

Anaplastic Lymphoma Kinase (ALK) Rearrangement-positive Lung Cancer with Transformation to Pleomorphic Carcinoma

Anaplastic Lymphoma Kinase (ALK) Rearrangement-positive Lung Cancer with Transformation to Pleomorphic Carcinoma

Updated Evidence on the Mechanisms of Resistance to ALK Inhibitors and Strategies to Overcome Such Resistance: Clinical and Preclinical Data

EML4‐ALK biology and drug resistance in non‐small cell lung cancer: a new phase of discoveries

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