Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer

Abstract

Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon, and pancreatic cancers combined. Current research suggests that standard chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT, and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway—involving AKT, CREB, Bcl-xL, survivin, and Bcl-2—downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that shRNA knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl play complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl.

Insights into the roles of hnRNP A2/B1 and AXL in non-small cell lung cancer

“…Among them, AXL expression was affected, indicating a potential interaction between hnRNP A2/B1 and AXL. Similar to the results reported by Linger et al (26), the current study revealed that positive expression of AXL was significantly higher in lung tumors than in paracancerous lung tissues. Additional investigation of clinical data indicated that AXL is highly associated with the prognosis of lung cancer, using univariate (but not multivariate) Cox regression models.…”

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

“…39,40 A more recent example is the receptor tyrosine kinase Axl, which has recently been shown to have a significant role in the malignant behavior of IBC cells 16 and has been previously revealed to block the induction of apoptosis through Akt and Bcl-xL. 41 However, our study is the first (to our knowledge) to directly address the molecular mechanisms that allow IBC cell survival in the context of ECM detachment. In addition, our findings suggest that targeting Bim-EL in a manner that promotes mitochondrial localization may be effective in the elimination of ECMdetached IBC cells.…”

Mer receptor tyrosine kinase is a therapeutic target in pre–B-cell acute lymphoblastic leukemia

“…25 To determine the differentially expressed genes, cuffdiff (with false-discovery rate ,0.001, fold-change . 18 Clonal populations of REH and 697 shMer cells were isolated by fluorescence-assisted single-cell sorting.…”

“…13 Transgenic Mer expression in mice results in the development of Tcell and biphenotypic lymphoblastic leukemia and lymphoma. 14 Mer activates antiapoptotic signaling proteins, including AKT and ERK1/2, [15][16][17] and promotes tumorigenic phenotypes in several other tumor types, including non-small-cell lung cancer, 18 melanoma, 19 and acute myeloid leukemia. 20 Here, we present data demonstrating increased Mer protein in E2A-PBX1…”