Activación de Src quinasa: implicaciones predictivas y pronósticas en pacientes con cáncer de colon

Abstract

Colorectal cancer (CRC) is a molecularly heterogeneous neoplasic disease that comprises a spectrum of tumors with a great variability in their natural history and susceptibility to different antineoplastic drugs. The identification of new prognostic and/or predictive biomarkers in this context can provide essential information on the molecular mechanisms that regulate the disease and provide new clinical tools to optimize prognostic stratification of patients or discover new therapeutic targets. Src belongs to a family of cytoplasmic non– receptor tyrosine kinases that play a key role in the regulation of different cellular processes related to carcinogenesis. Src activation has been associated with a more aggressive neoplastic phenotype and correlates with resistance to certain chemotherapeutic drugs, and preclinical studies have shown that this resistance can be reversed by pharmacological inhibition with specific inhibitors of Src. The aim of our study was to evaluate pSrc expression in a large cohort of patients with CRC and to assess its potential value as a prognostic and/or predictive biomarker in this context. With this purpose, pSrc expression was assessed in two cohorts of patients: a first cohort of 487 patients with surgically resected stage II-III colon cancer, treated or not with adjuvant chemotherapy, and a second cohort of 154 patients with metastatic CRC treated in first line with chemotherapy regimens containing fluoropyrimidines and oxaliplatin or irinotecan. pSrc expression was assessed in paraffin-embedded tumor samples by immunohistochemistry, and cases were classified by staining intensity in 4 categories:: no staining (0), weak (+1), moderate (+2), and intense (+3) staining. In the first cohort, high pSrc expression (+3) was significantly associated with decreased 5- year disease-free survival (39.2% vs 63.3% for patients with high (+3) vs low (0-2) pSrc expression, HR= 0.56; P = 0.005) and overall survival (OS) (57.5% vs 74.2%, HR= 0.55; P = 0.02). Multivariate analysis confirmed pSrc expression as a significant prognostic factor both for disease-free and overall survival, independent of other clinicopathological factors of known prognostic relevance for this tumor. However, no clear association was observed between pSrc expression and resistance to chemotherapy, as pSrc expression was shown to have a negative impact on survival regardless of the adjuvant treatment received. In the metastatic CRC cohort, positive pSrc expression (1-3) was associated with worse outcomes compared to the absence of expression (0), both in terms of progression-free survival (PFS rate at 12 months was 65.3% vs 73.8%, respectively, p=0.76) and of overall survival (OS rate at 3 years was 51.6% vs 60.9%, respectively, p=0.93). Nevertheless, these differences did not reach statistical significance. Moreover, there was also a non-significant trend towards worse response rates to chemotherapy in positive vs negative pSrc-expression tumors (43.5% vs 49.3%, respectively, p=0.52). In summary, the results of our study illustrate the relevance of Src activation in colon cancer biology, particularly in early stages of disease, and this is of great importance not only as it improves the prognostic stratification of patients to help in clinical decisions, but also because if opens new avenues for potential pharmacologic manipulation that may eventually improve patients' outcomes.