Promising clinical efficacy has been observed with receptor tyrosine kinase inhibitors (TKIs) particularly in lung and gastric cancers with mutations or amplifications in the targeted receptor tyrosine kinases (RTKs). However, the efficacy and the duration of the response to these inhibitors are limited by the emergence of drug resistance. Here, we report treatment of RTK-dependent lung and gastric cancer cell lines with TKIs increased protein levels of Bcl-2 and Bcl-xL. The combination of the Bcl-2 and Bcl-xL inhibitor ABT-263 and TKIs was superior to TKIs alone in reducing cell viability and capacity of resistant colony formation. Furthermore, resistant cells established with exposure of RTK-dependent cells to increasing concentrations of TKIs also express higher levels of Bcl-2 or Bcl-xL compared with their parental cells. The combination of inhibitors of PI3K/AKT, MEK/ERK, and Bcl-2/Bcl-xL effectively reduced the viability of resistant cells and inhibited tumor size in a xenograft model derived from resistant cells by inducing apoptosis. Our results define a generalizable resistance mechanism to TKIs and rationalize inhibition of Bcl-2 and Bcl-xL as a strategy to augment responses and blunt acquired resistance to TKIs in lung and gastric cancer.

Thoracic aortic aneurysm (TAA) results from dysregulated remodeling of the extracellular matrix mediated by matrix metalloproteinase (MMP) activity. Previous studies identified elevated membrane type-1 MMP (MT1-MMP) abundance and activity during TAA development and suggested aortic fibroblasts as a potential key source. Herein, we extended our understanding of the role of MT1-MMP during TAA development using various MT1-MMP transgenic mouse strains. MT1-MMP deficient (MT1-MMP^+/−) mice exhibited reduced MT1-MMP abundance, activity, and collagen volume fraction following TAA induction, concomitant with reduced aortic dilatation. TAA tissue from wild-type and MT1-MMP^+/− mice showed a similar reduction in thin collagen fibers, while the MT1-MMP^+/− mice displayed no change in thick collagen fibers. The role of fibroblast-derived MT1-MMP was examined using a conditional fibroblast-specific tamoxifen-inducible MT1-MMP knockout strain (FbMT1KO). TAA-induced changes in aortic diameter and MT1-MMP abundance were attenuated in FbMT1KO mice. Using aortic fibroblasts isolated from multiple mouse strains expressing different levels of MT1-MMP, a significant correlation between MT1-MMP abundance and TGF-β activation was observed. Importantly, treatment with MT1-MMP activity-neutralizing antibody or TGF-β neutralizing antibody resulted in the attenuation aortic dilatation. Together, these findings suggest that fibroblast-derived MT1-MMP is required for TAA development, in part through its ability to induce TGF-β signaling.

Background/Objective: Activity of SGK-1 has been associated with mechanical aspects of vascular remodeling and matrix stiffening has been a known characteristic of AAA. We hypothesis that VSMC-specific SGK-1 activity is vital to growth of AAA and contributes to progressive aortic stiffness. Methods: C57Bl/6 and SMC-SGK-1KO^+/− mice underwent AAA induction vs Sham on day 0. A subset of C57Bl/6 mice had pump implantation to treat with EMD638683. Aortic ultrasound images were obtained on Day 0 and Day 21 and analyzed for mechanical parameters. At terminal procedure the infrarenal aorta was harvested for immunoblot analysis. Results: At Day 21, C57Bl/6+AAA mice showed growth of 72.27% ± 2.2% versus the C57Bl/6+Sham (p < 0.0001) with associated 3.71 ± 1.15-fold increase in SGK-1 activity (p = 0.001). C57Bl/6+AAA+EMD mice demonstrated growth of 23.68% ± 2.82% (p = 0.0452) with no significant change in SGK-1 activity. SMC-SGK1-KO^+/−+AAA mice had growth of 28.20% ± 3.74% compared to SMC-SGK1-KO^+/−+Sham (p = 0.004) with increased SGK-1 activity (p = 0.0303). Radial strain was significantly reduced in the C57Bl/6+AAA (p = 0.0062) and C57Bl/6+AAA+EMD (p = 0.0135) when compared to C57Bl/6+Sham. Distensibility was significantly reduced in C57Bl/6+AAA (p = 0.01). Pulse propagation velocity (PPV) was significantly elevated in C57Bl/6+AAA mice (p < 0.0001) but inhibited by EMD therapy (p = 0.0007 vs. C57Bl/6+AAA). SMC-SGK1-KO^+/− +AAA mice showed significant reductions in radial strain (p = 0.0011) and distensibility (p = 0.0233) with a modest, but significant, increase in PPV (p = 0.0148). Conclusions: SGK-1 inhibition attenuated AAA growth and preserved vascular function. Targeting this pathway may provide a directed medical therapy for AAA and warrants further investigation.