Inhibition of autocrine HGF maturation overcomes cetuximab resistance in colorectal cancer

作者：Vivian Truong Jones, Ramona Graves‐Deal, Zheng Cao, Galina Bogatcheva, Marisol Ramirez, Sarah Harmych, James N. Higginbotham, Vineeta Sharma, Vishnu C. Damalanka, Claudia C. Wahoski, Neeraj Joshi, Maria Johnson Irudayam, Joseph T. Roland, Gregory D. Ayers, Qi Liu, Robert J. Coffey, James W. Janetka, Bhuminder Singh · 发表于：Cellular and Molecular Life Sciences · 年份：2024 · DOI：10.1007/s00018-023-05071-5 · 被引用次数：16 · 研究领域：Liver physiology and pathology、PI3K/AKT/mTOR signaling in cancer、Fibroblast Growth Factor Research

Although amplifications and mutations in receptor tyrosine kinases (RTKs) act as bona fide oncogenes, in most cancers, RTKs maintain moderate expression and remain wild-type. Consequently, cognate ligands control many facets of tumorigenesis, including resistance to anti-RTK therapies. Herein, we show that the ligands for the RTKs MET and RON, HGF and HGFL, respectively, are synthesized as inactive precursors that are activated by cellular proteases. Our newly generated HGF/HGFL protease inhibitors could overcome both de novo and acquired cetuximab resistance in colorectal cancer (CRC). Conversely, HGF overexpression was necessary and sufficient to induce cetuximab resistance and loss of polarity. Moreover, HGF-induced cetuximab resistance could be overcome by the downstream MET inhibitor, crizotinib, and upstream protease inhibitors. Additionally, HAI-1, an endogenous inhibitor of HGF proteases, (i) was downregulated in CRC, (ii) exhibited increased genomic methylation that correlated with poor prognosis, (iii) HAI-1 expression correlated with cetuximab response in a panel of cancer cell lines, and (iv) exogenous addition of recombinant HAI-1 overcame cetuximab resistance in CC-HGF cells. Thus, we describe a targetable, autocrine HAI-1/Protease/HGF/MET axis in cetuximab resistance in CRC.