Tumor microenvironment induces innate RAF-inhibitor resistance through HGF secretion

By R. Straussman, Teppei Morikawa, K. Shee, Michal Barzily-Rokni, Z. Qian, Jinyan Du, Ashli Davis, Margaret M. Mongare, Joshua Gould, Dennie T. Frederick and 9 more. Nature, 2012

1,464 citations recorded by the source corpus.

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)–AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/d51bc0a1730710ad5e74705bff1a2f756c61fc28

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Citations in the corpus

New horizons in tumor microenvironment biology: challenges and opportunities (2015, background): “Vemurafenib (PLX4032) BRAF-mutant melanoma; BRAFmutant colorectal cancer and glioblastoma Interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway Stroma-induced resistance; resistance to RAF inhibitors is induced by hepatocyte growth factor secreted from tumor-adjacent stromal cells [43,44]”
Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth (2015, background): “Proteomic analysis showed a correlation between stromal secretions of hepatocyte growth factor (HGF) and PLX4720 resistance [99].”
Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine (2017, background): “For example, resistance to small-molecule RAF inhibitors is conferred by tumor-associated fibroblasts that secrete hepatocyte growth factor (HGF) (5, 6).”
An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules (2013, background): “…levels of hepatocyte growth factor, which activates CRAF via MET in an autocrine fashion and circumvents dependence on BRAF (Corcoran et al., 2011; Straussman et al., 2012), and (2) the unresponsive CCL, SKMEL28, contains an activating mutation in EGFR , and enhanced EGFR signaling has been…”
EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, neutral): “A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Wargo JA, Golub TR. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.”
Lessons from the cancer genome. (2013, neutral): “Another group systematically screened stromal cell lines to identify those that secrete factors that confer resistance on adjacent cancer cells; the screen revealed that hepatocyte growth factor confers resistance to RAF inhibition (Straussman et al., 2012).”