Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC

CO-1686 is a novel, irreversible and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR including T790M while exhibiting minimal activity towards the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR mutated NSCLC tumor xenograft and transgenic models. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition (EMT) and demonstrated increased sensitivity to AKT inhibitors.

EGFR Modulates MicroRNA Maturation in Response to Hypoxia through Phosphorylation of AGO2

Epidermal growth factor receptor (EGFR) suppresses the maturation of specific tumour-suppressor-like miRNAs in response to hypoxic stress through phosphorylation of argonaute 2 (AGO2) at Tyr 393. The association between EGFR and AGO2 is enhanced by hypoxia, leading to elevated AGO2-Y393 phosphorylation, which in turn reduces the binding of Dicer to AGO2 and inhibits miRNA processing from precursor miRNAs to mature miRNAs.These findings suggest that modulation of miRNA biogenesis is important for stress response in tumour cells and has potential clinical implications.

Impact of EGFR Inhibitor in Non-Small Cell Lung Cancer on Progression-Free and Overall Survival: A Meta-Analysis

We examined the impact of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) on progression-free survival (PFS) and overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients with and without EGFR mutations.

EGFR-TKIs therapy statistically significantly delays disease progression in EGFR mutation-positive (EGFRmut+) patients but has no demonstrable impact on OS. EGFR mutation is a predictive biomarker of PFS benefit with EGFR-TKIs treatment in all settings. These findings support EGFR mutation assessment before initiation of treatment. EGFR-TKIs should be considered as front-line therapy in EGFRmut+ advanced NSCLC patients.

Preexisting interstitial lung disease is inversely correlated to tumor epidermal growth factor receptor mutation in patients with lung adenocarcinoma

Interstitial lung disease (ILD), especially idiopathic pulmonary fibrosis, has been shown to be associated with lung carcinogenesis. However, an association between epidermal growth factor receptor (EGFR) mutation status and preexisting ILD in patients with lung adenocarcinoma is unknown.

This study showed that patients with pulmonary adenocarcinoma and ILD had a lower probability of carrying tumor EGFR mutations.

A Randomized Phase 2 Study of Paclitaxel and Carboplatin with or without Conatumumab for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer

This study evaluated the efficacy, safety, and pharmacokinetics of conatumumab combined with paclitaxel-carboplatin (PC) as first-line treatment for advanced non-small-cell lung cancer (NSCLC).

Although well tolerated, the addition of conatumumab to PC did not improve outcomes in unselected patients with previously untreated advanced NSCLC.

Inhibition of TWIST1 Leads to Activation of Oncogene-Induced Senescence in Oncogene Driven Non-Small Cell Lung Cancer

We recently demonstrated that the basic helix-loop-helix transcription factor Twist1 cooperates with mutant Kras to induce lung adenocarcinoma in transgenic mouse models and that inhibition of Twist1 in these models led to Kras-induced senescence. In the current study, we show that silencing of TWIST1 in KRAS mutant human NSCLC cell lines as well as in in EGFR mutation driven and c-Met amplified NSCLC cell lines resulted in dramatic growth inhibition and either activation of a latent oncogene-induced senescence program or in some cases, apoptosis.These findings suggest that silencing of TWIST1 in oncogene driver dependent NSCLC represents a novel and promising therapeutic strategy.

Associations between Dietary Intake of Choline and Betaine and Lung Cancer Risk

Evidence from human and animal research indicates that choline metabolic pathways may be activated during a variety of diseases, including cancer. We report results of a case-control study of 2821 lung cancer cases and 2923 controls that assessed associations of choline and betaine dietary intakes with lung cancer. Our results suggest that choline and betaine intake, especially higher betaine intake, may be protective against lung cancer through mitigating the adverse effect of smoking.

Therapeutic effect of 188Re-MAG3-depreotide on non-small cell lung cancer in vivo an in vitro

This study shows that 188Re-MAG3-depreotide can inhibit the
proliferation and invasion of A549 cells and SPC-A1 cells. Treatment with 7.4MBq 188Re-MAG3-depreotide via tail vein can significantly
suppress the in vivo cancer growth and induce the apoptosis of cancer cells. These findings demonstrate that 188Re-MAG3-depreotide can
induce the apoptosis of NSCLC cells and directly kill the NSCLC cells, which provide evidence for the radiotherapy of NSCLC.

Impact of Epidermal Growth Factor Receptor and KRAS Mutations on Clinical Outcome in Resected Non-Small Cell Lung Cancer Patients

Surgery yields best results for non-small cell lung cancer (NSCLC) patients. Epidermal growth factor receptor (EGFR) and its downstream factor Kirsten rat sarcoma viral oncogene homolog (KRAS) are variably mutated in NSCLC. Such mutations predict clinical response to tyrosine kinase inhibitors. This study evaluated incidence and correlation of EGFR and KRAS mutations with clinicopathologic parameters and outcome in resected stage I to III NSCLC.

EGFR and KRAS mutations are frequent in adenocarcinomas and are not prognostic factors for survival. EGFR mutations could be used to identify patients suitable for adjuvant treatment with targeted therapy resulting in potentially improved outcomes.