Background: Neoadjuvant chemotherapy (NAC) has been proven to effectively improve the prognosis and long-term survival of patients with esophageal cancer (EC). But approximately 40% of patients are relatively insensitive to NAC. The mechanism underlying gene-induced resistance remains elusive.
Methods: We conducted a cohort of 13 NAC patients with different chemotherapy responses to identify gene mutations related to drug resistance by next-generation sequencing (NGS) of samples from patients with EC. We performed protein conformation on these mutant genes to figure out the possible mechanisms related to resistance.
Results: Our results indicated that missense mutations were commonly emerged in patients with partial response (PR) and stable disease (SD). Moreover, NOTCH1 gene, which is closely related to efficacy of chemotherapy, was further screened by comparing the changes in gene mutations before and after chemotherapy. Through protein conformational analysis, we found that missense mutations may cause changes in the ability of NOTCH1 receptor protein to bind ligands, which may cause abnormalities in the NOTCH1 pathway and make patients resistant to chemotherapy.
Conclusions: We analyzed the effect of platinum-based NAC on gene mutations in patients with EC and find that mutations in somatic genes, especially the NOTCH1 gene, may be associated with NAC resistance in EC.
Keywords: Drug resistance; NOTCH1; esophageal cancer (EC); neoadjuvant chemotherapy (NAC); next-generation sequencing (NGS).
2020 Translational Cancer Research. All rights reserved.