EGFR TKIs are not curative, and targeted resistance inevitably results in therapeutic failure. Additionally, there are numerous uncommon EGFR mutations that are insensitive to EGFR TKIs, and there is a lack of clinical strategies to overcome these limitations. EGFR TKI and mAbs target EGFR at different sites, and a combination regimen for delaying/preventing resistance to targeted therapy or obtaining more intensive inhibition for uncommon mutations at cellular, animal and human levels has been explored. This review critically focuses on a combination strategy for uncommon EGFR mutation-positive NSCLC, and discuss the preclinical data, clinical implications, limitations and future prospects of the combination strategy.

Third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, almonertinib and furmonertinib, overcome the mechanisms of resistance to first-generation inhibitors (such as gefitinib, erlotinib and icotinib) by incorporating an acrylamide group that alkylates the Cys797 of EGFR T790M. However, drug resistance is inevitable, even for third-generation TKIs. Screening for drug-resistant mutations by repeat biopsy and repeat gene sequencing is necessary after TKI treatment. Among various third-generation TKI-resistant mutations, secondary mutation of the L718 residue of EGFR exon 18 was found in approximately 8% of patients and is responsible for drug resistance in vitro and in vivo. Furthermore, there is limited clinical experience of targeted therapy for this mutation. Herein, we report for the first time that afatinib and cetuximab combination therapy can overcome such drug resistance.

Background the roles of RNA-binding proteins (RBPs) in esophageal cancer (EC) need elucidation. Materials and methods The gene expression profiles and clinical data of patients with EC were downloaded from the Xena database. Candidate genes were obtained by taking the union of RBP genes, KEGG pathway-related genes and differentially expressed RBP genes from cluster analysis. Hub genes were extracted by PPI network construction. Result We built a Cox proportional hazards regression model with 7 prognostic RBPs (TRMT2A, PDHA1, MPRIP, KRI1, IL17A, HSPA1A and HIST1H4J). The risk score of each patient in the internal and external dataset cohorts was calculated and then the patients were divided into two groups based on the median. There were significant differences between the RBP risk score and response to chemotherapy, with low-risk patients being more likely to achieve CR. Finally, the risk score was revealed to be significantly related to OS by univariate and multivariate analyses, and pathological stage could also be used independently to predict the prognosis of EC. Conclusion Our study indicated that the RBP signature could serve as a prognostic biomarker of EC and provide new insight into chemoresistance in EC patients.

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Background The prognosis and first-line treatment response of patients with borderline resectable esophageal squamous cell carcinoma are unsatisfactory. We are conducting the BRES-1 study to evaluate the safety and efficacy of camrelizumab combined with chemotherapy in patients with borderline resectable esophageal squamous cell carcinoma.Methods A total of 30 patients with borderline resectable esophageal squamous cell carcinoma will be enrolled in the BRES-1 study. These patients will undergo three stages of treatment: neoadjuvant therapy, surgery, and adjuvant therapy. Preoperative therapies will include camrelizumab, cisplatin and nab-paclitaxel. Patients will undergo esophagectomy 3–4 weeks after completing the neoadjuvant treatment. Three weeks after surgery, camrelizumab combined with chemotherapy will continue to be used for two cycles of maintenance therapy. Then, only camrelizumab will be administered for an entire year. The primary endpoint of this study will be pathological complete response (pCR).Discussion The BRES-1 trial will evaluate the efficacy and safety of camrelizumab combined with chemotherapy for patients with borderline resectable esophageal squamous cell carcinoma. Translational research will explore perioperative complications and drug-related adverse events.Trial registration ChiCTR, ChiCTR2200056728. Registered 11 February 2022. https://www.chictr.org.cn/index.aspx