With regard to the correlation between rearrangements and
With regard to the correlation between -rearrangements and thromboembolic events, Zer et al. reported a VTE rate of 36% in a cohort of 98 patients with ALK-positive NSCLC. Of note, VTE was also associated with shorter overall survival (HR: 5.71, =0.01) . Only few others have investigated NSCLC driver mutations as predictors of thromboembolic events, with highly variable results and VTE rates ranging from 8% to 47% . Differently, the rates of VTE in prospective clinical trials evaluating ALK targeting therapies were low (1–6%) possibly because of avoidance of platinum-based chemotherapy, differences in reporting adverse events and pre-existing medical conditions, which might contribute to underestimate the incidence of thromboembolic events, especially in second and subsequent lines of treatment.
Acute DIC is a rare complication in patients with lung cancer and associates with poor prognosis when the underlying cancer is not under control. More frequently, DIC presents with subclinical features and only occasionally occurs at diagnosis. Differently, our patient presented with acute onset of thrombotic DIC with venous and arterial thrombosis. In Tigecycline to other reports of patients with DIC and - or -positive NSCLC, our patient experienced two atypical manifestations during DIC, namely ischemic stroke and synchronous myocardial infarction, which ultimately conditioned the poor clinical outcome.
Mechanistically, the production of high quantity of mucin, which is a typical finding in -positive NSCLC may account, at least partially, for the higher incidence of thromboembolic events observed in such patients. Intriguingly, Murray and colleagues have recently discovered that heparin binds specifically to the ALK extracellular domain, thus providing further insights into the relationship between -rearrangements and thromboembolic events or hemostasis disorders in patients with -positive NSCLC .
Introduction New era of cancer therapy have commenced with the discovery, development and clinical achievements of tyrosine kinase inhibitors (TKIs) in recent decade. The course of treatment of non-small-cell lung cancer (NSCLC) patients has been changed and it has led to a major paradigm shift in oncology. The activation of anaplastic lymphoma kinase (ALK) in NSCLC through point mutations, genetic translocations, gene amplification, and gene fusions has been clinically targeted by FDA approved ALK inhibitors. Clinically existing small-molecule kinase inhibitors have demonstrated impressive therapeutic response and multi-targeted inhibition. To date, crizotinib (1st-generation, c-MET, ALK and ROS1 inhibitor) , , , , ceritinib (2nd-generation, ALK and ROS1 inhibitor) , , , and alectinib (2nd-generation, ALK+, GAK and LTK inhibitor) have demonstrated a pivotal role in the treatment of ALK-positive non-small cell lung cancer (ALK+ NSCLC). Since the discovery of crizotinib, several kinase inhibitors with substantial impact in the field of medical oncology have been approved by FDA (Fig. 1).
The c-ROS oncogene1 ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), located on chromosome 6q22.1, belongs to subfamily of tyrosine kinase insulin receptor genes. ROS1 is highly-expressed in a variety of tumor cells and the protein encoded by this gene has a tyrosine kinase activity. The identification of ROS1 receptor tyrosine kinase in a variety of human cancers such as ovarian cancer, angiosarcoma, NSCLC, cholangiocarcinoma, inflammatory, myofibroblastoma, glioblastoma multiform, and in spitzoid melanoma is well-documented as a culprit. The prevalence of ROS1 has made it an attractive and potentially relevant therapeutic target in cancer therapy , , , , , , , , , , , . ROS1 fusion genes have been characterized and recently identified in ∼1–2% of NSCLC, mainly in never smokers or light smokers , , . Inter-chromosomal translocations or intra-chromosomal deletions that result in chimeric genes involve fusion of the intracellular portion of ROS1 gene with a number of different genetic partners including CD74, SLC34A2 and FIG, , , , . These genetic rearrangements lead to fusion of proteins resulting in a constitutive kinase activity which in turn cause cellular transformation and drives cellular proliferation (Fig. 2) , .