Abstract
To improve treatment outcomes in non-small cell lung cancer (NSCLC), preclinical models that can better predict individual patient response to novel therapies are urgently needed. Using freshly resected tumor tissue, we describe an optimized ex vivo explant culture model that enables concurrent evaluation of NSCLC response to therapy while maintaining the tumor microenvironment. We found that approximately 70% of primary NSCLC specimens were amenable to explant culture with tissue integrity intact for up to 72 hours. Variations in cisplatin sensitivity were noted with approximately 50% of cases responding ex vivo Notably, explant responses to cisplatin correlated significantly with patient survival (P = 0.006) irrespective of tumor stage. In explant tissue, cisplatin-resistant tumors excluded platinum ions from tumor areas in contrast to cisplatin-sensitive tumors. Intact TP53 did not predict cisplatin sensitivity, but a positive correlation was observed between cisplatin sensitivity and TP53 mutation status (P = 0.003). Treatment of NSCLC explants with the targeted agent TRAIL revealed differential sensitivity with the majority of tumors resistant to single-agent or cisplatin combination therapy. Overall, our results validated a rapid, reproducible, and low-cost platform for assessing drug responses in patient tumors ex vivo, thereby enabling preclinical testing of novel drugs and helping stratify patients using biomarker evaluation. Cancer Res; 77(8); 2029-39. ©2017 AACR.
Highlights
Non–small cell lung cancer (NSCLC) is a leading cause of cancer death worldwide
Most patients receive combination chemotherapy based on clinical parameters of cisplatin or carboplatin with at least one other drug such as vinorelbine, gemcitabine, or paclitaxel
The highest proportion of nonviable tumors was within the adenocarcinoma subtype [$36% compared with $25% of squamous cell carcinoma (SCC) cases]
Summary
Non–small cell lung cancer (NSCLC) is a leading cause of cancer death worldwide. Patients with stage I–III tumors are surgically resected and given adjuvant chemotherapy or radiotherapy. Patients with stage IV disease receive palliative chemotherapy only unless they can be stratified for targeted therapy. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). A global industry is centered on assessing additional mono- or combinatorial treatments in NSCLC clinical trials. Despite this momentum, late-stage failures are a reality and there is less than 11% success in bringing a drug to market [6], attributable in part to nonpredictive preclinical drug platforms [7, 8]. Our data show that the explant platform can effectively predict patient response to therapy and can be used for monitoring clinically relevant biomarkers
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