STAT3 Is Activated by JAK2 Independent of Key Oncogenic Driver Mutations in Non-Small Cell Lung Carcinoma

Abstract

Constitutive activation of STAT3 is a common feature in many solid tumors including non-small cell lung carcinoma (NSCLC). While activation of STAT3 is commonly achieved by somatic mutations to JAK2 in hematologic malignancies, similar mutations are not often found in solid tumors. Previous work has instead suggested that STAT3 activation in solid tumors is more commonly induced by hyperactive growth factor receptors or autocrine cytokine signaling. The interplay between STAT3 activation and other well-characterized oncogenic “driver” mutations in NSCLC has not been fully characterized, though constitutive STAT3 activation has been proposed to play an important role in resistance to various small-molecule therapies that target these oncogenes. In this study we demonstrate that STAT3 is constitutively activated in human NSCLC samples and in a variety of NSCLC lines independent of activating KRAS or tyrosine kinase mutations. We further show that genetic or pharmacologic inhibition of the gp130/JAK2 signaling pathway disrupts activation of STAT3. Interestingly, treatment of NSCLC cells with the JAK1/2 inhibitor ruxolitinib has no effect on cell proliferation and viability in two-dimensional culture, but inhibits growth in soft agar and xenograft assays. These data demonstrate that JAK2/STAT3 signaling operates independent of known driver mutations in NSCLC and plays critical roles in tumor cell behavior that may not be effectively inhibited by drugs that selectively target these driver mutations.

miR-204 suppresses non-small-cell lung carcinoma (NSCLC) invasion and migration by targeting JAK2

“…The de-regulation of the JAK expression is associated with several aspects of tumorigenesis, including increased proliferation and reduced apoptosis (Qian et al, 2011). JAK2 protein is overexpressed in several immune diseases and a variety of cancers, including NSCLC (Looyenga et al, 2012). In this study, the overexpression of JAK2 in NSCLC was suppressed by the miR-204 mimics.…”

Bioinformatic analysis reveals a pattern of STAT3-associated gene expression specific to basal-like breast cancers in human tumors

“…Because the aberrant immunological processes in basal-like cancers are so commonly associated with difficulty in treatment and increased mortality, STAT3 signaling may be a promising target for subtype-specific breast cancer treatment. With the increasing number of therapeutic molecules specifically targeted toward STAT3 coming through clinical trials (23)(24)(25), the inclusion of these compounds in subtype-specific breast cancer treatment may be a promising avenue. This analysis yields a farreaching protein interaction network and potential associations with inflammation and aberrant immunological cell recruitment, a common problem associated with many basal-like cancers and a prognostic factor when assessing patient survival (17).…”

Identification of Subsets of Genetic Alterations in KRAS-mutant Lung Cancer using Association Rule Mining

“…STAT3 is hyperactive in some lung cancers [45]. This hyperactivity might be due to enhanced signaling from RTKs, cytokines or JAK kinases (altered in 11% of KRAS-mutant tumors) or by inactivating mutations in PTPRs [42,46,47].…”