Identification of novel driver mutations of the discoidin domain receptor 2 (DDR2) gene in squamous cell lung cancer of Chinese patients

Abstract

BackgroundAlthough many of the recently approved genomically targeted therapies have improved outcomes for patients in non–small-cell lung cancer (NSCLC) with lung adenocarcinoma, little is known about the genomic alterations that drive lung squamous cell cancer (SCC) and development of effective targeted therapies in lung SCC is a promising area to be further investigated. Discoidin domain receptor 2 (DDR2), is a novel receptor tyrosine kinases that respond to several collagens and involved in tissue repair, primary and metastatic cancer progression.MethodsExpression of DDR2 mRNA was analyzed in 54 lung SCC tissues by qRT-PCR. Over-expression approaches were used to investigate the biological functions of DDR2 and its’ mutations in lung SCC cells. Conventional Sanger sequencing was used to investigate the mutations of DDR2 gene in 86 samples. The effect of DDR2 and its’ mutations on proliferation was evaluated by MTT and colony formation assays; cell migration and invasion was evaluated by trasnwell assays. Lung SCC cells stably transfected with pEGFP-DDR2 WT, pEGFP-DDR2-S131C or empty vector were injection into nude mice to study the effect of DDR2 and its’ mutation on tumorigenesis in vivo. Protein and mRNA expression levels of E-cadherin and MMP2 were determined by qRT-PCR and western blot analysis. Differences between groups were tested for significance using Student’s t-test (two-tailed).ResultsIn this study, we found that DDR2 mRNA levels were significantly decreased in 54 lung SCC tissues compared with normal lung tissues. Moreover, there were 3 novel DDR2 mutations (G531V, S131C, T681I) in 4 patients and provide the mutation rate of 4.6% in the 86 patients with lung SCC. The mutation of S131C in DDR2 could promote lung SCC cells proliferation, migration and invasion via inducing MMP-2, but reducing E-cadherin expression.ConclusionsThese data indicated that the novel DDR2 mutation may contribute to the development and progression of lung SCC and this effect may be associated with increased proliferation and invasiveness, at least in part, via regulating E-cadherin expression.

Extracellular matrix component signaling in cancer

“…The initial study concluded that gain of functions mutations in DDR2 are oncogenic and provided the first targetable mutations in lung SCC [116] and hence caused much excitement in the field. However, the study did not address the contribution of wild-type DDR2 to oncogenesis, and while several more recent studies have confirmed the occurrence of DDR2 mutations in different patient populations [122][123][124], it is far from clear whether the mutations are indeed oncogenic and their roles in lung SCC cell signalling are undefined [125]. Notably, in other studies, some of the 'oncogenic' DDR2 mutants either seemed to play tumour suppressive functions [101], or did not contribute to cell proliferation in lung SCC cell lines [126].…”

Clinicopathologic Features of Advanced Squamous NSCLC

“…85,87 However, a range of DDR2 mutations have been identified, not all of which are definitely proven to be oncogenic. 87,88 To date, clinical trials of agents targeting DDR2 have been hampered by excessive toxicity, especially in patients with sqCLC. 89 Lack of efficacy has also been noted.…”

Bone Metastases in Lung Cancer. Potential Novel Approaches to Therapy

“…Of the two members of this small family, DDR1 is expressed in tumor cells of epithelial origin and DDR2 in tumor-associated stroma (37). In addition, DDR2 is mutated in squamous cell cancer (4.4%) (38) and in lung AD (2-5%) (29), whereas DDR1 overexpression is associated with poor prognosis in NSCLC (39,40). Interestingly, partial responses have been achieved using combinatorial therapies with dasatinib, a multitarget tyrosine kinase inhibitor that also blocks DDR2 (41).…”