ALK and IGF-1R as independent targets in crizotinib resistant lung cancer

Wilson, Christabel; Nimick, Mhairi; Nehoff, Hayley; Ashton, John C.

doi:10.1038/s41598-017-14289-w

Cited by 23 publications

(16 citation statements)

References 24 publications

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“… 16 As reported, IGF-1R overexpression can be found in many types of cancers, such as colorectal cancer and lung cancer. 22 – 24 A couple of reports identified that inhibition of IGF-1R exerts anti-tumor effects, therefore, IGF-1R has been suggested as a novel therapeutic target for GC patients. 16 …”

Section: Discussionmentioning

confidence: 99%

miR-598 acts as a tumor suppressor in human gastric cancer by targeting IGF-1R

Liu¹,

Yang

Wang³

2018

OTT

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BackgroundIn recent years, the aberrant expression of miR-598 in tumorigenesis has been demonstrated, as well as the fact that the IGF-1R pathway is also involved in the development of human gastric cancer (GC). The present study aimed to investigate the molecular mechanisms underlying miR-598-regulated IGF-1R expression in human GC.Materials and methodsWe analyzed the expression of miR-598 and IGF-1R in GC samples and cells, and evaluated the clinical significance of miR-598 and IGF-1R in GC patients. Furthermore, in vitro and in vivo assays were used to investigate the molecular mechanisms of miR-598 and IGF-1R.ResultsmiR-598 expression was frequently downregulated in GC tissues and cells, and significantly correlated with poor prognosis, vascular invasion, TNM stage, and lymph node metastases as well as IGF-1R expression. The overexpression of miR-598 obviously inhibited cell proliferation, migration, invasion, and induced cell cycle arrest in the G1/S phase, and increased the apoptosis of GC cells. The overexpression of miR-598 also significantly inhibited ERK1/2 and Akt phosphorylation level. In vivo assay validated the inhibitory effect of miR-598 on tumor growth. Further studies showed that miR-598 inhibited IGF-1R protein expression by directly targeting its 3′-UTR. Besides, over-expression of IGF-1R reversed the inhibitory effects of miR-598, while suppression of IGF-1R expression showed inverse effects.ConclusionmiR-598 suppresses GC cell proliferation, migration and invasion by directly targeting IGF-1R expression. Thus, miR-598 may be a useful target for GC patients.

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Section: Discussionmentioning

confidence: 99%

miR-598 acts as a tumor suppressor in human gastric cancer by targeting IGF-1R

Liu¹,

Yang

Wang³

2018

OTT

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“…Crizotinib-resistant (CR-H3122) cells were generated as described in Wilson et al . 35 and were maintained in 0.8 µM of crizotinib. Briefly, H3122 cells were cultured with increasing concentrations of crizotinib starting from 0.4 µM for 24 h followed by 0.56 µM for next 24 h. Cells were then maintained in 0.80 µM from 3 rd day to 4 months.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer

Shrestha

Nimick

Dass

et al. 2019

Sci Rep

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Anaplastic lymphoma kinase (ALK) rearrangement, a key oncogenic driver in a small subset of non-small cell lung cancers, confers sensitivity to ALK tyrosine kinase inhibitors (TKIs). Crizotinib, a first generation ALK-TKI, has superiority to standard chemotherapy with longer progression-free survival and higher objective response rate. However, clinical benefit is limited by development of resistance, typically within a year of therapy. In this study the combined effect of crizotinib and the MEK inhibitor selumetinib was investigated in both crizotinib naïve (H3122) and crizotinib resistant (CR-H3122) ALK-positive lung cancer cells. Results showed that combination treatment potently inhibited the growth of both H3122 and CR-H3122 cells, resulting from increased apoptosis and decreased cell proliferation as a consequence of suppressed downstream RAS/MAPK signalling. The drug combination also elicited a greater than 3-fold increase in Bim, a mediator of apoptosis, and p27, a cyclin dependent kinase inhibitor compared to crizotinib alone. The results support the hypothesis that combining MEK inhibitors with ALK inhibitor can overcome ALK inhibitor resistance, and identifies Bim, PARP and CDK1 as druggable targets for possible triple drug therapy.

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“…Increased activation of other HER family members beyond EGFR, including HER2 and HER3 may also mediate acquired resistance to crizotinib [ 59 ]. In addition, upregulation of IGF1R signaling has been recently identified as an important bypass pathway, and blockade of IGF1R activity resensitized crizotinib resistant cells to ALK inhibition in pre-clinical models [ 60 , 61 ]. Finally, amplification of KIT also represents a potential mechanism of crizotinib resistance, though increased expression of KIT alone does not appear to be sufficient to confer resistance [ 51 ].…”

Section: Introductionmentioning

confidence: 99%

The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC)

et al. 2018

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Lung cancer is the leading cause of death by cancer in North America. A decade ago, genomic rearrangements in the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase were identified in a subset of non-small cell lung carcinoma (NSCLC) patients. Soon after, crizotinib, a small molecule ATP-competitive ALK inhibitor was proven to be more effective than chemotherapy in ALK-positive NSCLC patients. Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, are approved for use as a first-line therapy in these patients, where ALK rearrangement is currently diagnosed by immunohistochemistry and in situ hybridization. The clinical success of these three ALK inhibitors has led to the development of next-generation ALK inhibitors with even greater potency and selectivity. However, patients inevitably develop resistance to ALK inhibitors leading to tumor relapse that commonly manifests in the form of brain metastasis. Several new approaches aim to overcome the various mechanisms of resistance that develop in ALK-positive NSCLC including the knowledge-based alternate and successive use of different ALK inhibitors, as well as combined therapies targeting ALK plus alternative signaling pathways. Key issues to resolve for the optimal implementation of established and emerging treatment modalities for ALK-rearranged NSCLC therapy include the high cost of the targeted inhibitors and the potential of exacerbated toxicities with combination therapies.

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ALK and IGF-1R as independent targets in crizotinib resistant lung cancer

Cited by 23 publications

References 24 publications

miR-598 acts as a tumor suppressor in human gastric cancer by targeting IGF-1R

miR-598 acts as a tumor suppressor in human gastric cancer by targeting IGF-1R

Mechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer

The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC)

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