Intriguingly our laboratory has shown

Intriguingly, our laboratory has shown that the I638F kinase domain mutant, unlike the L63V and G505 mutants, is incapable of receptor autophosphorylation and activation of its downstream effector SHP-2 when exposed to collagen stimulation. These data indicate that I638F is a loss of function mutation that eliminates receptor activation and effector signaling. Consistent with this idea, this kinase domain mutant was able to abrogate the growth suppressive properties of wildtype DDR2 in HEK293 1080 6 grown in 3D collagen gels. It is not clear as to the mechanisms by which receptor depletion (by RNA interference) or kinase inhibitor treatment promotes cytotoxicity in lung SCC cell lines bearing the I638F kinase inactive DDR2 mutant. One potential explanation is that DDR2 may possess additional kinase-independent oncogenic functions that are important for fuelling lung cancer cell growth. Alternatively, in the absence of intrinsic autophosphorylation capacity, DDR2 may be susceptible to transphosphorylation and activation by other tyrosine kinases such as SRC or insulin-like growth factor-1R.,, It should be noted that collagen accumulates in the lung during tumor progression, which may impact the biological properties of DDR2., In this respect, transgenic mouse models of mutant DDR2-driven lung SCC will undoubtedly shed light on the role of this receptor in the context of the in vivo lung tumor microenvironment. In addition to a direct role in regulating tumor cell growth, conflicting literature also exists for the role of DDR2 in supporting metastatic growth. In particular, two groups have examined the function of DDR2 in the host stromal compartment as a regulator of cancer metastasis. In one study, Zhang et al. found that DDR2 expression is enriched in tumor-associated endothelial cells in both colon carcinoma and melanoma. Using a transgenic mouse model that is deficient for DDR2 as the host in an experimental system for metastatic melanoma, the authors showed that pulmonary metastasis was significantly reduced in the mutant mice versus control. This was attributed to a decrease in angiogenesis as a result of downregulation of proangiogenic genes such as VEGFR2 and upregulation antiangiogenic components including Ang-1. In contrast, Badiola et al. demonstrated the opposite effect in hepatic metastases of colon carcinoma. In their model, downregulation of DDR2 in the host mice generated a prometastatic niche in the liver leading to increased vascular endothelial growth factor and transforming growth factor-β expression and metastases. Collectively, these studies emphasize the complex nature of DDR2 interactions in both tumor and stromal cells and highlights the potential challenges associated with targeting this receptor.
DDR2 TARGETED THERAPY There are several candidate small molecule inhibitors that selectively target DDR2. As discussed above, the multikinase inhibitors dasatinib, imatinib, and nilotinib block DDR2 kinase activity in an adenosine triphosphate (ATP)-competitive manner with varying levels of potency. Hammerman et al. showed that a panel of lung SCC DDR2 mutants is selectively sensitive to these inhibitors. A recent report by the same group showed that prolonged exposure of dasatinib to lung cancer cell lines that were dasatinib sensitive and DDR2 dependent resulted in acquired drug resistance in vitro. Interestingly, using massively parallel sequencing, the authors identified two distinct mechanisms of dasatinib resistance. One mechanism is the acquisition of the gatekeeper T654I mutation on DDR2 that increases the affinity for ATP and prevents drug binding. The second is loss of NF1 expression through a splice site mutation. NF1 is a negative regulator of Ras and the authors showed that loss of this protein results in the maintenance of ERK1/2 survival signals even when DDR2 is inhibited by dasatinib, conferring drug resistance. This data suggest that to overcome potential drug resistance that may arise in lung SCC dasatinib trials, a combination regimen including an ERK1/2 pathway inhibitor may be necessary.