Pkm2 Expression May Predict Chemosensitivity to Cisplatin-Based Chemotherapy in Metastatic Non-Small Cell Lung Cancer (NSCLC)

ABSTRACT Background Tumor cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase (PKM2). Overexpression of PKM2 has been correlated with cisplatin resistance in cell lines and xenograft models. We evaluated the predictive significance of PKM2 in patients with stage IV NSCLC. Methods PKM2 mRNA expression was analysed by RT-qPCR in microdissected FFPE primary tumors from 305 NSCLC patients (148 as training set and 157 as experimental set) treated with front-line cisplatin-based chemotherapy and 85 patients treated with a non-platinum doublet (as validation set). Results The patients' characteristics were all typical for metastatic NSCLC (median age 61 years, 86% males, 64% adenocarcinomas and 28% squamous cell carcinomas, ECOG PS 0-1: 83%). PKM2 was successfully amplified in all specimens. Progression Free Survival (PFS) was significantly lower in patients with overexpression of PKM2 (4.9 vs. 6.4 months for high and low expression, respectively, p = 0.028) in the training set and the results were confirmed in the experimental set (3.7 vs. 5.9 months, p = 0.006). Similarly, median overall survival (mOS) was significantly decreased in patients with upregulation of PKM2 in both sets: 10.1 vs 17.0 months in the training set (p = 0.01) and 8.3 vs 16.8 months in the experimental sets (p = 0.003), for high and low expression, respectively. In contrast, there was no statistical difference in terms of PFS (5.6 vs. 5.9 months, p = 0.431) and mOS (9.8 vs. 10.1 months, p = 0.512) between low and high PKM2 expression in the validation group. Multivariate analysis revealed that PKM2 high mRNA expression could be emerged as an independent factor associated with decreased PFS (training set: HR = 1.6, p = 0.02; experimental set: HR = 2.1, p = 0.013) and mOS (training set: HR = 1.9, p = 0.02; experimental set: HR = 2.6, p = 0.001), but not in the validation set (PFS: HR = 1.1, p = 0.627; mOS: HR = 0.96, p = 0.495). Conclusions These results indicate that the PKM2 mRNA expression may be used as a predictive factor for sensitivity to cisplatin-based chemotherapy. Disclosure All authors have declared no conflicts of interest.