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NHE9 induces chemoradiotherapy resistance in esophageal squamous cell carcinoma by upregulating the Src/Akt/β-catenin pathway and Bcl-2 expression.

ABSTRACT: Recently, we found that NHE9 mRNA was upregulated in chemoradiotherapy (CRT)-resistant esophageal squamous cell carcinoma (ESCC); however, the underlying mechanisms were unclear. Here, we aimed to clarify the functional contribution of NHE9 to CRT resistance, understand the molecular basis of NHE9-dependent resistance in ESCC, and identify potential therapeutic targets. Our results showed that NHE9 prevented CRT-induced apoptosis. Importantly, we found that RACK1 is a novel binding partner of NHE9 and that NHE9-dependent induction of CRT resistance requires the activation of RACK1-associated Src/Akt/β-catenin signaling. Moreover, upregulated Bcl-2 protein was also observed in cells exhibiting NHE9-induced CRT resistance. A higher NHE9 level was associated with a poor response to CRT and less decrease in T and N stage in ESCC patients. Furthermore, combining either Dasatinib or ABT-737 with CRT significantly reduced tumor volume, and the response to CRT was restored when these inhibitors were used together with CRT in a xenograft nude mouse model with NHE9 overexpression. Taken together, our findings demonstrate that NHE9 can be an effective predictor of CRT response and may be useful in the development of targeted therapies for CRT-resistant ESCC.

SUBMITTER: Chen J

PROVIDER: S-EPMC4494947 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThe safety and feasibility of preoperative pembrolizumab combined with chemoradiotherapy (PPCT) for resectable esophageal squamous cell carcinoma have been confirmed by the prior Preoperative Anti-PD-1 Antibody combined with Chemoradiotherapy for Locally Advanced Squmous Cell Carcinoma of Esophageus (PALACE)-1 trial. Potential therapeutic benefit was also observed with a pathologic complete response rate of 55.6% after PPCT. We will conduct the multicenter single-arm PALACE-2 study to investigate the efficacy and to further confirm the safety of PPCT (ClinicalTrials.gov ID: NCT04435197).MethodsA total of 143 patients with previously untreated, locally advanced, and surgically resectable esophageal squamous cell carcinoma (T2 through T4a, N0 through N+, M0) will be enrolled in PALACE-2. Main exclusion criteria are autoimmune disease, interstitial lung disease, ongoing immunosuppressive therapy, and having received chemotherapy, radiotherapy, target therapy, or immune therapy for this or any other malignancies. Positive programmed cell death ligand 1 expression is not mandatory for enrollment. Patients will receive PPCT, which includes concurrent pembrolizumab (200 mg on day 1 and day 22), carboplatin (area under the curve = 2, once a week for 5 weeks), nab-paclitaxel (50 mg/m2, once a week for 5 weeks), and radiotherapy (23 fractions of 1.8 Gy, 5 fractions a week). Esophagectomy will be performed within 4 to 6 weeks after the completion of PPCT.ResultsThe primary end point is the rate of pathologic complete response. Secondary outcome measures are 3-year disease-free survival rate, 3-year overall survival rate, R0 resection rate, and adverse events during neoadjuvant and perioperative periods.ConclusionsPPCT was preliminarily demonstrated to be safe, feasible, and to provide potential therapeutic benefits by the PALACE-1 trial. The subsequent multicenter PALACE-2 study will investigate the efficacy and further confirm the safety of PPCT for locally advanced, resectable esophageal squamous cell carcinoma.

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NHE9 induces chemoradiotherapy resistance in esophageal squamous cell carcinoma by upregulating the Src/Akt/β-catenin pathway and Bcl-2 expression.

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