ABSTRACT
Epidermal growth factor receptor (EGFR) -mutant advanced non-small cell lung cancer (NSCLC) was previously regarded as a cold tumor according to tumor immune microenvironment (TIME) . However, recent studies have found that EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment can transform the host immunity from immunosuppressive to immunosupportive state, bringing new hope for immunotherapy. There are four main therapeutic strategies for patients after EGFR-TKIs acquired resistance: immunotherapy alone (Im) , immunotherapy plus chemotherapy (Im+C) , immunotherapy plus antiangiogenic drugs (Im+A) , and immunotherapy combined with antiangiogenic drugs and chemotherapy (Im+A+C) . Among them, the efficacy of Im is extremely limited, being significantly lower than that of chemotherapy alone, while there is still scarce evidence for the efficacy of Im+A with few clinical studies. The combination of Im+C and Im+A+C shows better efficacy than chemotherapy alone. Im+A+C has a superior clinical outcome to Im+C. Additionally, the EGFR L858R mutation subgroup benefits more from Im+C than the EGFR 19 del mutation subgroup. The T790M-negative subgroup has a greater benefit from Im+A+C than the T790M-positive subgroup. In general, the strategy of combining immunotherapy with chemotherapy and/or an antiangiogenic drug represents a novel and promising method for treating EGFR-mutant NSCLC after EGFR-TKI failure.
ABSTRACT
EGFR?TKIs have changed the landscape of metastatic NSCLC treatment with a significant improvement in survival of EGFRm patients compared to wild?type EGFR. Even with the newer third generation EGFR TKIs like, Osimertinib, which has proven efficacy against the resistance mutation of EGFRm T790M, progression eventually occurs. There are limited treatment options for patients with metastatic EGFRm NSCLC with other acquired resistance. Therefore, novel therapeutic combination strategies are being researched to overcome potential resistance to EGFR?TKI?targeted therapy. The ICIs targeting the programmed cell death?1 pathway in patients with EGFRm NSCLC were greatly anticipated based on preclinical studies showing increased PD?L1 expression. In clinical settings, this increased expression did not translate into a survival benefit. Treatment with ICIs failed to positively affect EGFRm patients because of multiple reasons: nonsynonymous tumor mutational burden, lower PD?L1 expression in tumors, and cancer cells utilizing alternate immune escape mechanisms. The NCCN guidelines currently do not recommend immunotherapy in patients with metastatic EGFRm NSCLC. Recently, a subgroup analysis in the IMpower150 study provided a signal for overall survival of atezolizumab with bevacizumab plus chemotherapy in EGFRm?TKI progressed patients. Based on these encouraging findings, several combinations of ICIs and EGFR?TKIs are being evaluated in TKI?failed EGFRm patients. These regimens might provide a favorable therapeutic effect by combining higher response rates of TKIs and durable disease control of ICIs. However, further research is warranted to understand the exact underlying molecular and cellular mechanisms responsible for the clinical benefits. In this article, we explored the TKI failed metastatic EGFRm NSCLC, reviewed the available clinical data of ICI use in metastatic EGFRm NSCLC, and discussed its emerging role as a combination regimen in this patient population
ABSTRACT
Objective To investigate the expression and activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), its upstream molecule, epidermal growth factor receptor (EGFR), and downstream transcription factor, Ets-like protein 1 (ELK-1), in lesions of psoriasis vulgaris, and to evaluate the relationship between ERK pathway and psoriasis vulgaris. Methods Tissue samples were obtained from the lesions of 40 patients with psoriasis vulgaris and normal skin of 20 normal human controls. Immunohistochemistry and Western blot were performed to detect the expressions of phosphorylated ERK1/2, EGFR and ELK-1 in the tissue samples.Results As immunohistochemistry showed, the integrated optical density (IOD) of p-ERK1/2, p-EGFR and p-ELK-1 was 269.85 ± 57.96, 136.88 ± 30.33 and 237.61 ± 56.29 respectively in the psoriatic lesions, significantly higher than that in the normal controls ( 140.24 ± 24.42, 110.66 ± 28.99 and 119.04 ± 21.99, respectively, all P ＜ 0.05). A positive correlation was observed between the expression of p-EGFR and p-ERK1/2(r = 0.57, P ＜ 0.05) and between that of p-ERK1/2 and p-ELK-1 (r=0.72,P＜0.05) in psoriatic lesions.Conclusion The enhanced signal transduction through phosphorylated EGFR→ERK1/2→ELK-1 pathway may play a certain role in the pathophysiological process of psoriasis vulgaris.
ABSTRACT
BACKGROUND: Epidermal growth factor receptors (EGFR) have been reported to be absent in melanomas. But recently, the presence of EGFR on melanocytic cells was reported to be a marker of malignant transformation. OBJECTIVE: Our purpose was to investigate the presence of EGFF in melanocytic lesions and to determine whether EGFR presence correlates with the potential or malignant transformation of melanocytic cells. METHODS: We performed the immunohistochemical studies to reveal immunoreactivity of EGFR in 7 compound nevi, 10 intradermal nevi, and four melanomas using the Vectastain ABC immunoperoxidase stain system. RESULTS: Although the intensity of staining was slightly variable, all melanocytic cell types in the studied lesions of compound nevi, intradermal nevi, and melanoms had immunoreactive EGFR. Intense staining far EGFR of all nucleated layers of keratinocytes overlying a melanocytic lesion was also seen. But in the melanoma cells, the staining intensity was modarately deereased. CONCLUSION: Although we found no correlation of EGFR with the potential for malignancy in melanocytic lesions, the high level of expression within nevocytes and lesional keratinocytes suggests EGFR or transforming growth factor a, by acting through the EGFR, plays a role in the pathogenesis, maintenance, or evolution or these lesions.