Abstract 1159: A novel HGF-MET paracrine signaling pathway promotes growth and resistance to chemotherapy in lung cancer

Abstract

Lung cancer is a leading cause of deaths from cancer among men and women worldwide with an estimated 1.5 million deaths each year. Available molecularly targeted therapies benefit a limited number of patients and even in these patients acquired resistance is a major impediment to effective therapeutic response. To address the need for additional therapeutic targets, we used a unique approach to identify and target tumor-stroma paracrine crosstalk pathways in non-small cell lung cancer (NSCLC). To explore paracrine crosstalk in NSCLC, we analyzed transcriptomes of specific stromal and epithelial compartments that were sorted from Kras driven mouse model of NSCLC. Transcriptome analysis and computational modeling of multi-cellular network identified potential tumor-stroma crosstalk signaling pathways. We have selected the hepatocyte growth factor (HGF)-MET tyrosine kinase receptor signaling pathway because both HGF and MET are associated with poor survival in many cancer types including lung cancer. Notably, we identified reprogrammed intratumoral macrophages as unique source of HGF, while the expression of MET receptor was confined to tumor epithelial compartment. Importantly, we have observed elevated HGF in chemoresistant tumors both in mouse and human. Previous studies have implicated MET receptor amplification or mutations as the main mechanism of acquired resistance to EGFR TKIs, but little is known about the contribution of HGF ligand-dependent activation of MET signaling in NSCLC growth and resistance to chemotherapeutic regimens that are widely used. We have used a combination of culture experiments and in vivo genetic approaches to show that macrophage-derived HGF interacts with the MET receptor on tumor epithelial cells in a paracrine fashion, to activate downstream signaling pathways that promote tumor progression and mediate resistance to standard chemotherapies. Our investigations on this relatively unexplored HGF-MET paracrine interaction as a key mechanism of resistance to standard-of-care chemotherapeutic regimens-and not just EGFR targeted therapies-have the potential to benefit the NSCLC population as whole rather than a small subset of patients. Citation Format: Hyejin Choi, Ding Cheng Gao, Sharrell B. Lee, Anna Durrans, Seongho Ryu, Olivier Elemento, Stephen Wong, Nasser K. Altorki, Vivek Mittal. A novel HGF-MET paracrine signaling pathway promotes growth and resistance to chemotherapy in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1159. doi:10.1158/1538-7445.AM2014-1159

CRTAC1 enhances the chemosensitivity of non-small cell lung cancer to cisplatin by eliciting RyR-mediated calcium release and inhibiting Akt1 expression

“…However, solid tumors in different regions have different sensitivities to anticancer drugs, and the triggered signaling pathways are complex, resulting in decreased sensitivity of some cancer cells [ 19 ]. Abnormal activation or inhibition of intracellular signal transduction pathways is related to the resistance of tumor cells to chemotherapy [ 20 ]. However, tumor cells with high sensitivity to cisplatin can specifically inhibit survival signals and trigger cell death signals.…”

Effect of BRAF‑mediated PI3K/Akt/mTOR pathway on biological characteristics and chemosensitivity of NSCLC A549/DDP cells

“…Correlation of the expression of special genes with tumor stages and the prognosis of patients has gradually become a major direction of lung cancer research ( 17 ). Prior evidence supports that one of the important reasons for the resistance of tumor cells to chemotherapy relates to the abnormal activation or inhibition of intracellular signal transduction pathways ( 18 ). For instance, the PI3K/Akt/mTOR signaling pathway has been revealed to be commonly upregulated in multiple cancer cells ( 19 , 20 ).…”