Association of tumor mutation burden and epidermal growth factor receptor inhibitor history with survival in patients with metastatic stage III/IV non-small-cell lung cancer: A retrospective study

OBJECTIVES: Lung cancer is the leading cause of cancer-related deaths worldwide. However, factors associated with the survival of patients with advanced non-small-cell lung cancer (NSCLC) who received only hospice care are largely unclear. In this study, we aimed to determine the prognostic factors correlated with survival in patients with advanced NSCLC who had undergone hospice care only. METHODS: A total of 102 patients with recurrent stage III/IV NSCLC after traditional treatment failure were investigated. Survival was measured from the date of enrollment to December 2019 or the time of death. Tumor tissues were collected, and DNA sequencing was performed to identify somatic mutations. Data on clinical factors of patients were collected and analyzed by univariate and multivariate analyses. Overall survival analysis was conducted using the Kaplan-Meier method. RESULTS: The 6-month, 1-year, and 2-year overall survival rates of the 102 patients with metastatic NSCLC were 17.65%, 3.92%, and 0.98%, respectively. The median overall survival of the 102 patients was 3.15 months. Tumor location in the peripheral lung, epidermal growth factor receptor (EGFR) inhibitor history, low tumor mutation load, adenocarcinoma, and poor performance status score were associated with prolonged survival compared with tumor location in the central lung, no EGFR inhibitor history, high tumor mutation load, squamous cell carcinoma, and good performance status score (p=0.045, p=0.003, p=0.045, p=0.021, and p=0.0003, respectively). CONCLUSIONS: EGFR inhibitor treatment history and tumor mutation load are risk factors for the overall survival of patients with stage III/IV NSCLC who have undergone only hospice care. These results provide a critical clinical basis for further study of nontraditional anti-tumor responses induced by EGFR inhibitors.

Discovery of WS-157 as a highly potent, selective and orally active EGFR inhibitor

EGFR tyrosine kinase inhibitor (EGFR-TKI) has been used successfully in clinic for the treatment of solid tumors. In the present study, we reported the discovery of from our in-house diverse compound library, which was validated to be a potent and selective EGFR-TKI. showed excellent inhibitory activities against EGFR (IC = 0.81 nmol/L), EGFR (IC = 1.2 nmol/L) and EGFR (IC = 1.1 nmol/L), but was less effective or even inactive against other nine kinases. also displayed excellent antiproliferative activities against a panel of human cancer cell lines, and exhibited the ability to reduce colony formation and wound healing the same as gefitinib. We found that upon oral administration showed better anti-tumor activity in A431 bearing xenograft mouse models compared to gefitinib. In addition, showed better intestinal absorption than gefitinib and had favorable pharmacokinetic properties and microsomal metabolic stability in different species. These studies indicate that has strong antitumor activity and , and could be used for the development of anti-lung cancer agent targeting EGFR.

Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data

Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.

Molecular Targeted Therapy of Head and Neck Cancer: Promising Molecular Targets of Post-Epidermal Growth Factor Receptor Era / 대한이비인후과학회지

Head and neck squamous cell carcinoma (HNSCC) affects over half a million people worldwide. Despite advances in biology and medicine, only half of the patients are alive in 5 years. The epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of HNSCC cases, and it is correlated with poor responses to therapy and worse prognosis. Multiple therapies targeting this pathway have been tested. However, only a minority of patients has showed meaningful responses to these agents and almost all who do develop acquired tumor resistance after a few months of treatment. Recently, a significant interest has focused on identifying mechanisms of acquired and de novo resistance of EGFR blockage. In addition, other inhibitors of EGFR that interfere with known molecular pathways activated in HNSCC have been studied extensively, either as single agents or in combination with other treatment modalities. Here we review some of EGFR resistance mechanisms and briefly discuss new molecular therapeutic strategies to overcome that resistance in HNSCC.

Treatment of Cultured Sebocytes with an EGFR Inhibitor Does Not Lead to Significant Upregulation of Inflammatory Biomarkers

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are being used to treat malignancies originating from epithelia. Unfortunately, blocking the EGFR pathway leads to various side effects, most frequently acneiform eruptions. OBJECTIVE: To probe the mechanism underlying this side effect, we investigated the effect of EGFR inhibitors on cultured sebocytes. METHODS: To examine the effects of an EGFR inhibitor (cetuximab, Erbitux(R) 10 ng/ml) and the effects of EGFR ligands, such as epidermal growth factor (EGF, 10 ng/ml) and transforming growth factor-alpha (TGF-alpha, 5 ng/ml), on the production of inflammatory cytokines in cultured sebocytes, we used reverse transcriptase-polymerase chain reaction, immunocytofluorescence and Western blots. Outcomes included the expression of interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-alpha), peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and EGFR. RESULTS: There were no significant differences in the expression of IL-1, IL-6, TNF-alpha, PPAR-gamma and EGFR between (a) groups treated with an EGFR inhibitor or an EGFR ligand and (b) the control group, except for a significant increase in the expression of IL-1 in the EGF-treated group. CONCLUSION: EGFR inhibitors and EGFR ligands do not provoke the expression of inflammatory biomarkers in cultured sebocytes. The role of the sebaceous glands in EGFR inhibitor-induced acneiform eruption should be investigated more thoroughly.

Targeted Therapies and Radiation for the Treatment of Head and Neck Cancer / 대한방사선종양학회지

PURPOSE: The purpose of this review is to provide an update on novel radiation treatments for head and neck cancer. RECENT FINDINGS: Despite the remarkable advances in chemotherapy and radiotherapy techniques, the management of advanced head and neck cancer remains challenging. Epidermal growth factor receptor (EGFR) is an appealing target for novel therapies in head and neck cancer because not only EGFR activation stimulates many important signaling pathways associated with cancer development and progression, and importantly, resistance to radiation. Furthermore, EGFR overexpression is known to be portended for a worse outcome in patients with advanced head and neck cancer. Two categories of compounds designed to abrogate EGFR signaling, such as monoclonal antibodies (Cetuximab) and tyrosine kinase inhibitors (ZD1839 and OSI-774) have been assessed and have been most extensively studied in preclinical models and clinical trials. Additional TKIs in clinical trials include a reversible agent, CI-1033, which blocks activation of all erbB receptors. Encouraging preclinical data for head and neck cancers resulted in rapid translation into the clinic. Results from initial clinical trials show rather surprisingly that only minority of patients benefited from EGFR inhibition as monotherapy or in combination with chemotherapy. In this review, we begin with a brief summary of erbB- mediated signal transduction. Subsequently, we present data on prognostic-predictive value of erbB receptor expression in HNC followed by preclinical and clinical data on the role of EGFR antagonists alone or in combination with radiation in the treatment of HNC. Finally, we discuss the emerging thoughts on resistance to EGFR blockade and efforts in the development of multiple-targeted therapy for combination with chemotherapy or radiation. Current challenges for investigators are to determine (1) who will benefit from targeted agents and which agents are most appropriate to combine with radiation and/or chemotherapy, (2) how to sequence these agents with radiation and/or cytotoxic compounds, (3) reliable markers for patient selection and verification of effective blockade of signaling in vivo, and (4) mechanisms behind intrinsic or acquired resistance to targeted agents to facilitate rational development of multi-targeted therapy. Other molecular-targeted approaches in head and neck cancer were briefly described, including angioenesis inhibitors, farnesyl transferase inhibitors, cell cycle regulators, and gene therapy SUMMARY: Novel targeted therapies are highly appealing in advanced head and neck cancer, and the most promising strategy to use them is a matter of intense investigation.

Targeted therapies in the treatment of gastric cancer / 中国癌症杂志

Gastric cancer is one of the most common malignancies in the digestive system.Most of the patients with gastric cancer have advanced disease at the time of diagnosis.Chemotherapy is still the mainstay of treatment for advanced gastric cancer,but efficacy of chemotherapy was modest.Molecular targeted therapies have emerged as a novel approach to the treatment of both hematological and solid tumors in recent years.The understanding of molecular biological mechanisms underlying the formation,progression and metastasis in advanced gastric cancer has enabled us to use the new approach to treat this disease in clinical practice.These therapeutic strategies include targeting EGFR signal transduction pathway,anti-angiogenesis,targeting NF-?B signal transduction pathway and cyclin-dependent kinase inhibitors.In this review,a brief introduction of the current status of the molecular targeted therapies in the treatment of gastric cancer was presented.Bevacizumab,anti-VEGF monoclonal antibody targeting the angiogenesis pathway has been approved for the treatment of colorectal cancer by FDA,has been reported to show effectiveness in metastatic gastric cancer when combined with cytotoxic agents.Inhibition of NF-?B signal transduction pathway such as PS-341(proteasome inhibitor,bortezomib) approved for the treatment of refractory or recurrent multiple myeloma by FDA has also been used to combine with chemotherapy for gastric cancer.There are also encouraging reports on the combination of standard chemotherapy with Cetuximab,Matuzumab,Gefitinib,Erlotinib and Trastuzumab which target the EGFR and HER2 signal transduction pathways.Flavopiridol is a cyclin-dependent kinase inhibitor with low molecullar weight that aims at the regulatory process of the cell cycle but this needs further clinical trial.