PKM2 as a biomarker for sensitivity to oxaliplatin-based chemotherapy in metastatic colorectal cancer (mCRC).

Abstract

434 Background: Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase (PKM2), which is a key enzyme that regulates aerobic glycolysis in tumor cells. Use of RNA interfering (RNAi) targeting PKM2 significantly inhibits tumor growth when combined with cisplatin in xenograft models. We evaluated the predictive significance of PKM2 in patients with mCRC treated with oxaliplatin- based chemotherapy in the first-line setting. Methods: FFPE primary tumors from 140 mCRC patients were analyzed for PKM2 mRNA expression by RT-qPCR. The analysis was performed with a set of primers and probes which amplify only the M2 isoform. Results: The patients' characteristics were all typical for mCRC (median age 65 years, 61% males, 75% colon cancer 25% rectal cancer, 41% undifferentiated tumors, 21% mucinous features). PKM2 was successfully amplified in all specimens. Time to tumor progression (TTP) was significantly lower in patients with overexpression of PKM2 (6.7 vs. 9.1 months for high and low expression, respectively, p=0.004). Similarly, median overall survival (mOS) was significantly decreased in patients with upregulation of PKM2 (21.9 vs. 30.2 months for high and low expression, respectively, p=0.004). Multivariate analysis revealed PKM2 high mRNA expression (HR: 1.7, p=0.005) and the presence of undifferantited tumors (HR: 2.2, p<0.0001) as independent prognostic factors for decreased TTP. Similarly, PKM2 high mRNA expression (HR: 1.8, p=0.005) and the presence of undifferantited tumors (HR: 2.5, p<0.0001) were revealed as independent prognostic factors for decreased mOS. Conclusions: These results provide evidence that the PKM2 mRNA expression could be used as a predictive factor for sensitivity to oxaliplatin-based chemotherapy. The results should be validated prospectively in an independent patient cohort. No significant financial relationships to disclose.