Genetic Ablation of Epidermal EGFR Reveals the Dynamic Origin of Adverse Effects of Anti-EGFR Therapy

“Cancer patients treated with anti-EGFR (epidermal growth factor receptor) drugs often develop a dose-limiting pruritic rash of unknown etiology. The aims of our study were to define causal associations from a clinical study of cutaneous and systemic changes in patients treated with gefitinib and use these to develop and characterize a mouse model that recapitulates the human skin rash syndrome caused by anti-EGFR therapy. We examined the patients’ plasma before and after treatment with gefitinib and documented changes in chemokines and leukocyte counts associated with the extent of rash or the presence of pruritus. We established a parallel mouse model by ablating EGFR in the epidermis. These mice developed skin lesions similar to the human rash. Before lesion development, we detected increased mRNA expression of chemokines in the skin associated with early infiltration of macrophages and mast cells and later infiltration of eosinophils, T cells, and neutrophils.”


VeriStrat Assay May Help Select NSCLC Patients for Second-Line Therapy

“VeriStrat, a serum-based protein assay, can help select which patients with non–small cell lung cancer (NSCLC) who are not known to have epidermal growth factor receptor (EGFR) mutations might benefit from an EGFR-targeted agent, according to a study described at the 2013 Best of ASCO Los Angeles meeting by Heather A. Wakelee, MD, Associate Professor of Medicine, Stanford University, Palo Alto, California.”


Funding Strategy Needed to Support EGFR Mutation Testing in Canada

Funding represents a decisive barrier to the nationwide implementation of genetic testing for a key lung cancer mutation in Canada, a recent study finds. Patients with non-small cell lung cancer (NSCLC) who have a mutation in the EGFR gene frequently benefit from treatment with EGFR inhibitors. AstraZeneca, makers of the EGFR inhibitor gefinitinb (Iressa), reimbursed Canadian laboratories for offering EGFR mutation testing to patients with advanced non-squamous NSCLC for 12 months. EGFR mutation testing was rapidly adopted into routine clinical practice in Canada. However, testing rates dropped sharply once the reimbursement program ended. Researchers conclude that a national strategy is needed to provide resources for continued EGFR testing.


Afatinib is FDA-Approved: What It Means For NSCLC Patients


On July 12, the FDA announced that it had approved the targeted therapy afatinib (Gilotrif) for the treatment of metastatic non-small cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR) gene.

EGFR mutations occur in about 10 to 15 percent of all NSCLC patients. The overexpression of the EGFR protein caused by the mutation leads to rapid cell division in tumors. Prior to the approval of afatinib, patients in the United States could only take erlotinib (Tarceva) to combat the EGFR mutation. The third major drug available to treat EGFR-mutated tumors, gefitinib (Iressa) has not yet been approved by the United States but is readily available in many other countries. Erlotinib has consistently outperformed gefitinib, so its lack of availability in the U.S. is no huge loss. Continue reading…


USP8 Is a Novel Target for Overcoming Gefitinib Resistance in Lung Cancer

Our purpose was to test ubiquitin-specific peptidase 8 (USP8) as a potential therapeutic target for gefitinib-resistant and -sensitive non-small cell lung cancer (NSCLC). Our results show for the first time that the inhibition of USP8 activity or reduction in USP8 expression can selectively kill NSCLC cells. We propose USP8 as a potential therapeutic target for gefitinib-resistant and -sensitive NSCLC cells.


Evidence of Epidermal Growth Factor Receptor Expression in Uveal Melanoma: Inhibition of Epidermal Growth Factor-Mediated Signalling by Gefitinib and Cetuximab Triggered Antibody-Dependent Cellular…

“Despite advances in surgery and radiotherapy of uveal melanoma (UM), many patients develop distant metastases that poorly respond to therapy. Improved therapies for the metastatic disease are therefore urgently needed. Expression of the epidermal growth factor receptor (EGFR), a target of kinase inhibitors and humanised antibodies in use for several cancers, had been reported. Forty-eight human UMs were analysed by expression profiling. Signalling was tested in three EGFR expressing UM cell lines by Western blotting using phosphorylation specific antibodies for EGFR and the downstream mediators AKT (v-akt murine thymoma viral oncogene homolog) and extracellular signal-regulated kinase (ERK). Evidence for signalling in tumours was obtained through the application of a UM-specific EGF-signature. The EGFR specific kinase inhibitor, Gefitinib and the humanised monoclonal antibody, Cetuximab, were tested for their effect on EGFR signalling. Natural killer cell mediated antibody-dependent cellular cytotoxicity (ADCC) and tumour necrosis factor α (TNF-α) release was analysed for Cetuximab.”


Synergistic Effects of Metformin Treatment in Combination with Gefitinib, a Selective EGFR Tyrosine Kinase Inhibitor, in LKB1 Wild-type NSCLC Cell Lines

EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) are effective against lung cancer, but clinical resistance to these agents has developed. Metformin is a widely used antidiabetic drug and also displays significant growth-inhibitory and proapoptotic effects in several cancer models, alone or in combination with chemotherapeutic drugs.

Metformin and gefitinib are synergistic in LKB1 wild-type NSCLC cells. However, further studies are required to investigate better the effect of metformin action on the RAS/RAF/MAPK pathway and the best context in which to use metformin in combination with molecular targeted agents.


USP8 Is a Novel Target for Overcoming Gefitinib Resistance in Lung Cancer

Common treatment modalities for non–small cell lung cancer (NSCLC) involve the EGF receptor-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib. However, the vast majority of treated patients acquire resistance to EGFR-TKIs, due, in large part, to secondary mutations in EGFR or amplification of the MET gene. Our purpose was to test ubiquitin-specific peptidase 8 (USP8) as a potential therapeutic target for gefitinib-resistant and -sensitive non–small cell lung cancer (NSCLC).

Our results show for the first time that the inhibition of USP8 activity or reduction in USP8 expression can selectively kill NSCLC cells. We propose USP8 as a potential therapeutic target for gefitinib-resistant and -sensitive NSCLC cells.


Patients with Drug-Resistant Lung Cancer Might Benefit from New Drug CO-1686

Patients with non-small cell lung cancer (NSCLC) who have mutations in the EGFR gene often improve significantly when treated with EGFR inhibitors like erlotinib (Tarceva) or gefitinib (Iressa). However, in virtually all cases, patients eventually develop resistance to these drugs. Resistance to EGFR inhibitors is frequently associated with patients developing an additional mutation in the EGFR gene called T790M. Hope for these patients may come from a new EGFR inhibitor designed to target the T790M mutation, called CO-1686. Preliminary results from an ongoing early clinical trial of CO-1686 show that the drug shrank tumors in at least a subset of patients with EGFR-mutant advanced NSCLC who were resistant to EGFR inhibitors and carried the T790M mutation.