Combined inhibition of insulin-like growth factor-1 receptor enhances the effects of gefitinib in a human non-small cell lung cancer resistant cell line

Qi, Hui; Shen, Zan; Fan, Li hong

doi:10.3892/etm.2011.324

Cited by 13 publications

(8 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, p-4EBP1, p-TFEB levels remain the same or slightly upregulated in sensitive cells upon TKI treatments, a pattern different than that in p-S6K1, suggesting that S6K1 activation is mTOR-independent ( Fig.3H ). AKT and IGF-IR pathways were reported to confer resistance to EGFR-TKIs ( 10 , 28 - 31 ). We found that p-AKT was reduced by gefitinib in both cell lines, whereas p-IGF-IR was moderately increased in both sensitive and resistant cells, suggesting a compensatory activation of IGF-IR signaling due to blockade of EGFR pathway ( Fig.3I ).…”

Section: Resultsmentioning

confidence: 99%

S6K1 blockade overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer

Shen

Wang

et al. 2020

Oncogene

View full text Add to dashboard Cite

The development of resistance to EGFR Tyrosine kinase inhibitors (TKIs) in NSCLC with activating EGFR mutations is a critical limitation of this therapy. In addition to genetic alterations such as EGFR secondary mutation causing EGFR-TKI resistance, compensatory activation of signaling pathways without interruption of genome integrity remains to be defined. In this study, we identified S6K1/MDM2 signaling axis as a novel bypass mechanism for the development of EGFR-TKI resistance. The observation of S6K1 as a candidate mechanism for resistance to EGFR TKI therapy was investigated by interrogation of public databases and a clinical cohort to establish S6K1 expression as a prognostic/predictive biomarker. The role of S6K1 in TKI resistance was determined in in vitro gain-and-loss of function studies and confirmed in subcutaneous and orthotopic mouse lung cancer models. Blockade of S6K1 by a specific inhibitor PF-4708671 synergistically enhanced the efficacy of TKI without showing toxicity. The mechanistic study showed the inhibition of EGFR caused nuclear translocation of S6K1 for binding with MDM2 in resistant cells. MDM2 is a downstream effector of S6K1-mediated TKI resistance. Taken together, we present evidence for the reversal of resistance to EGFR TKI by the addition of small molecule S6K1/MDM2 antagonists that could have clinical benefit.

show abstract

Section: Resultsmentioning

confidence: 99%

S6K1 blockade overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer

Shen

Wang

et al. 2020

Oncogene

View full text Add to dashboard Cite

show abstract

“…AG1024, which prevents autophosphorylation of IGF-1R, synergizes with gefitinib to produce pro-apoptotic and anti-proliferative effects in vitro in previously gefitinib-resistant NSCLC cells. 59 In mutant KRAS lung adenocarcinoma, IGF's downstream PI3K/AKT signaling is thought to be involved with both this gefitinib resistance and re-sensitization by interacting with the anti-apoptotic Ku70 and pro-apoptotic BAX proteins. 60 …”

Section: Lung Cancermentioning

confidence: 99%

Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance

Denduluri

Idowu

Wang³

et al. 2015

Genes & Diseases

278

221

View full text Add to dashboard Cite

One of the greatest obstacles to current cancer treatment efforts is the development of drug resistance by tumors. Despite recent advances in diagnostic practices and surgical interventions, many neoplasms demonstrate poor response to adjuvant or neoadjuvant radiation and chemotherapy. As a result, the prognosis for many patients afflicted with these aggressive cancers remains bleak. The insulin-like growth factor (IGF) signaling axis has been shown to play critical role in the development and progression of various tumors. Many basic science and translational studies have shown that IGF pathway modulators can have promising effects when used to treat various malignancies. There also exists a substantial body of recent evidence implicating IGF signaling dysregulation in the dwindling response of tumors to current standard-of-care therapy. By better understanding both the IGF-dependent and -independent mechanisms by which pathway members can influence drug sensitivity, we can eventually aim to use modulators of IGF signaling to augment the effects of current therapy. This review summarizes and synthesizes numerous recent investigations looking at the role of the IGF pathway in drug resistance. We offer a brief overview of IGF signaling and its general role in neoplasia, and then delve into detail about the many types of human cancer that have been shown to have IGF pathway involvement in resistance and/or sensitization to therapy. Ultimately, our hope is that such a compilation of evidence will compel investigators to carry out much needed studies looking at combination treatment with IGF signaling modulators to overcome current therapy resistance.

show abstract

“…For example, Qi et al demonstrated that IGF-1 receptor blockade acts synergistically with gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, in gefitinib-resistant NSCLC [106]. In addition, Kim et al showed that an IGF-1 receptor tyrosine kinase inhibitor was cytotoxic to NSCLC cells which expressed wild-type, but not those with EGFR mutations [107].…”

Section: Laboratory Evidence and The Basis For Further Clinical Trialsmentioning

confidence: 99%

The Links Between Insulin Resistance, Diabetes, and Cancer

2012

View full text Add to dashboard Cite

The growing epidemic of obesity has resulted in a large increase in multiple related diseases. Recent evidence has strengthened the proposed synergistic relationship between obesity-related insulin resistance (IR) and/or diabetes mellitus (DM) and cancer. Within the past year, many studies have examined this relationship. Although the precise mechanisms and pathways are uncertain, it is becoming clear that hyperinsulinemia and possibly sustained hyperglycemia are important regulators of not only the development of cancer but also of treatment outcome. Further, clinical decision-making regarding the treatment of choice for DM will likely be impacted as we learn more about the non-metabolic effects of the available hyperglycemic agents. In our review, we endeavored to synthesize the recent literature and provide a concise view of the journey from macro-level clinical associations to specific mechanistic relationships being elucidated in cell lines and animal models.

show abstract

Combined inhibition of insulin-like growth factor-1 receptor enhances the effects of gefitinib in a human non-small cell lung cancer resistant cell line

Cited by 13 publications

References 27 publications

S6K1 blockade overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer

S6K1 blockade overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer

Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance

The Links Between Insulin Resistance, Diabetes, and Cancer

Contact Info

Product

Resources

About