Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: Implications for future therapeutic approaches

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Abstract

Although the role of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has been most extensively studied in hematopoietic cells and hematologic malignancies, it is also activated in epithelial tumors, including those originating in the lungs and head and neck. The canonical pathway involves the activation of JAK following ligand binding to cytokine receptors. The activated JAKs then phosphorylate STAT proteins, leading to their dimerization and translocation into the nucleus. In the nucleus, STATs act as transcription factors with pleiotropic downstream effects. STATs can be activated independently of JAKs, most notably by c-Src kinases. In cancer cells, STAT3 and STAT5 activation leads to the increased expression of downstream target genes, leading to increased cell proliferation, cell survival, angiogenesis, and immune system evasion. STAT3 and STAT5 are expressed and activated in head and neck squamous cell carcinoma (HNSCC) where they contribute to cell survival and proliferation. In HNSCC, STATs can be activated by a number of signal transduction pathways, including the epidermal growth factor receptor (EGFR), α7 nicotinic receptor, interleukin (IL) receptor, and erythropoietin receptor pathways. Activated STATs are also expressed in lung cancer, but the biological effects of JAK/STAT inhibition in this cancer are variable. In lung cancer, STAT3 can be activated by multiple pathways, including EGFR. Several approaches have been used to inhibit STAT3 in the hopes of developing an antitumor agent. Although several STAT3-specific agents are promising, none are in clinical development, mostly because of drug delivery and stability issues. In contrast, several JAK inhibitors are in clinical development. These orally available, ATP-competitive, small-molecule kinase inhibitors are being tested in myeloproliferative disorders. Future studies will determine whether JAK inhibitors are useful in the treatment of HNSCC or lung cancer.

Introduction

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway was first defined as the signal transduction pathway downstream of cytokine receptors. This pathway is essential in normal physiology, as it mediates responses to cytokines in hematopoietic cells. The pathway is also responsible for signaling downstream of several hormone receptors, including the growth hormone and prolactin receptors.

Early studies in Drosophila indicated that the JAK-STAT pathway was important in human leukemia; hyperactivation of Drosophila JAK (Tum1, hop) led to leukemia-like hematopoietic defects (Luo et al., 1995). Likewise, enhanced JAK activation in humans leads to neoplastic transformation in hematologic malignancies. Somatic mutations resulting in constitutive JAK2 activation [JAK2 V617F and translocation-ets-leukemia (TEL)-JAK2] have been identified in myeloproliferative disorders (MPDs) and leukemia in humans (Tefferi, 2006). Furthermore, inhibiting JAK leads to cancer regression, confirming its role in neoplastic progression (Hedvat et al., 2009).

In addition to its clear role in hematologic malignancies, the JAK-STAT pathway is also activated in many solid tumors, including head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC). It is important to define the role of this pathway in these solid tumors, as better therapies are desperately needed for these malignancies, and new therapeutic agents that target both JAK and STAT are being developed. Indeed, JAK kinase inhibitors are already being tested in clinical trials. This review will briefly outline the regulation and downstream effects of the JAK/STAT signaling pathway in cancer and then focus on its specific roles in head and neck and lung cancers.

Section snippets

JAK proteins as non-receptor tyrosine kinases that mediate cytokine receptor signaling

The JAK family of 110–140 kDa non-receptor tyrosine kinases consists of four known members in humans: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAKs are nearly ubiquitously expressed, with the exception of JAK3, which is only expressed in hematopoietic, vascular smooth muscle, and endothelial cells (Paukku and Silvennoinen, 2004). However, no published studies have examined the expression of JAK proteins in HNSCC or lung cancer tissues, although we have recently found that HNSCC cell lines

STATs as transcription factors and their diverse downstream effectors

The STAT family of transcription factors consists of seven proteins in humans (STAT1–STAT4, STAT5A, STAT5B, and STAT6) that are all encoded by separate genes. They function in normal human physiology and development but also regulate oncogenic signaling in many different tumor types (Turkson et al., 2004a). STAT2, STAT4, and STAT6 function in the development of T-cells and in IFN-gamma signaling. They are activated by a small number of cytokines. STAT1, STAT3, and STAT5 are activated in diverse

Negative feedback loops regulating the JAK-STAT pathway following cytokine stimulation

There are three negative feedback loops that regulate STAT function after cytokine signaling: SH2-containing phosphatases (SHPs), which inactivate JAK; protein inhibitor of activated STAT3 (PIAS), which is a negative regulator of STAT3 transcription; and suppressors of cytokine signaling (SOCS) (Huang, 2007) (Fig. 2). Eight SOCS proteins have been identified (SOCS-1–7 and CIS), and they regulate JAK-STAT signaling by inhibiting JAK kinase activity, facilitating the proteasomal degradation of

Non-canonical JAK-STAT signaling pathways

In addition to the classical JAK-STAT pathway described above (Fig. 1), alternative functions for JAK and STAT have been described. Recently, Gough et al. (2009) demonstrated that H-Ras-dependent oncogenic transformation was dependent upon mitochondrial STAT3. Unlike the v-Src-dependent transformation, the H-Ras-dependent transformation's requirement for STAT3 was independent of its tyrosine phosphorylation, its DNA-binding domain, its SH2 domain, and nuclear translocation. However,

JAK/STAT in head and neck squamous cell carcinoma

A number of findings suggest that the JAK/STAT pathway contributes to HNSCC disease progression. The expression and phosphorylation of STAT3, but not STAT1, are elevated in HNSCC cells, as compared with normal epithelial cells (Grandis et al., 1998). In addition, HNSCC specimens also have higher levels of STAT3 than normal tissue (Grandis et al., 2000). In a study of patients with tobacco chewing-mediated HNSCC, activation of STAT3 was identified as an early event in head and neck

STAT3 and STAT5 expression in lung cancer

Activated STAT3 (nuclear pSTAT3) is expressed in about 55% of NSCLC tumors, as measured by immunohistochemical analyses (Gao et al., 2007, Haura et al., 2005, Sanchez-Ceja et al., 2006). pSTAT3 expression was more common in patients with smaller tumors (Gao et al., 2007), a limited smoking history, and adenocarcinoma (Haura et al., 2005). There was an inverse correlation between pSTAT3 expression and tumor apoptosis. However, pSTAT3 expression did not correlate with overall survival (Cortas et

JAK/STAT inhibition in lung cancer

Several studies have addressed the biological effects of JAK or STAT inhibition in NSCLC. Inhibiting STAT3 using anti-sense or dominant-negative constructs led to apoptosis in some NSCLC cell lines, and the degree of baseline STAT3 activation did not affect the sensitivity of the cells to STAT3 inhibition (Song et al., 2003). Likewise, JAK kinase inhibition using pyridone 6 did not cause significant cytotoxicity in NSCLC cell lines in vitro (Johnson et al., 2007).

Signaling pathways affecting JAK/STAT in lung cancer

One way to address the inconsistent biologic effect of JAK/STAT inhibition in NSCLC is to understand the signaling pathways both up- and downstream from JAK/STAT. EGFR is an important growth factor receptor in NSCLC that, when activated, leads to STAT3 activation (Kluge et al., 2009). Expression of pSTAT3 correlates with that of pEGFR in NSCLC patients (Haura et al., 2005). Furthermore, EGFR can activate STAT3 in both JAK-independent (Leaman et al., 1996, Olayioye et al., 1999, Song et al., 2003

STAT inhibitors

Although there continue to be efforts to target STAT5 in hematopoietic disorders and malignancies, constitutive activation of STAT3 and the compelling evidence of its involvement in tumorigenesis has made STAT3 the central focus as a therapeutic target in solid tumors. Several strategies have been employed in the inhibition of STAT3, including disruption of its SH2 domain-mediated dimerization, inhibition of its DNA-binding activity, and inhibition protein–protein interaction with the

JAK inhibitors in early clinical development

Given that JAK2 is important for the progression of Bcr-Abl-negative myeloproliferative disorders (MPDs), nearly all of the preclinical testing and clinical trials of JAK inhibitors have been conducted in these diseases. Both the constitutively active mutant JAK2 (JAK2V617F) and wt JAK2 mediate cytokine and growth factor-induced survival in MPDs. Inhibition of JAK2 leads to reduced proliferation and increased apoptosis in cell lines and explants from patients with MPDs with both mutant (JAK2

Conclusions

Preclinical studies support targeting the JAK-STAT pathway in head and neck and lung cancers. A number of JAK inhibitors are already undergoing clinical trials, but no STAT inhibitors have been sufficiently developed for clinical evaluation. Current studies suggest that JAK-STAT pathway inhibition will likely be done in combination with other molecular targeted agents against complementary signal transduction pathways (Dent et al., 2009). While the studies remain promising, significant hurdles

Acknowledgements

The authors thank Dorinda Smith and Brenda Robinson for administrative support. We thank Kate J. Newberry in the Department of Scientific Publications for editorial assistance.

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