Predictive and prognostic value of phosphorylated c-KIT and PDGFRA in advanced non-small cell lung cancer harboring ALK fusion.

Abstract

Secondary KIT gene amplification leads to tyrosine kinase inhibitor resistance in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC). The presence of the 4q12 amplicon causes the activation of downstream mast/stem cell growth factor receptor Kit (c-Kit) or platelet-derived growth factor receptor α (PDGFRA) signaling pathways. Therefore, in the present study, the association between the functional proteins phosphorylated c-Kit (p-c-Kit) and phosphorylated PDGFRA (p-PDGFRA) and the prognosis of ALK fusion NSCLC was investigated. Advanced stage NSCLC samples with ALK fusion were tested for their p-c-Kit and p-PDGFRA content by immunohistochemical staining, and for its association with crizotinib efficacy and the survival of the patients. Of 64 eligible ALK-positive patients with NSCLC, 30 (46.9%) were p-c-Kit-positive and 10 (15.7%) were p-PDGFRA-positive. Brain metastases were more common in ALK-positive cases that were p-PDGFRA-positive compared with those who were p-PDGFRA-negative. ALK-positive patients treated with crizotinib, who exhibited high levels of p-c-Kit had significantly lower progression-free survival times than those with low levels. In addition, the patients with high levels of p-c-Kit exhibited lower overall survival times than those with low levels. Furthermore, multivariate analysis indicated that high levels of p-c-Kit in patients with ALK fusion was the only significant predictive factor for crizotinib efficacy and was a prognostic factor for poor overall survival time. However, no statistically significant difference was observed in the survival of patients with different p-PDGFRA levels. p-PDGFRA was more frequently expressed in the ALK-positive cases with brain metastasis. c-Kit signaling activation may be associated with poor efficacy of crizotinib and poor prognosis in advanced ALK fusion NSCLC.