Crosstalk to Stromal Fibroblasts Induces Resistance of Lung Cancer to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Abstract

Purpose: Lung cancers with epidermal growth factor receptor (EGFR)-activating mutations show good clinical response to gefitinib and erlotinib, selective tyrosine kinase inhibitors (TKI) to EGFR, but these tumors invariably develop drug resistance. Host stromal cells have been found to have a considerable effect on the behavior of cancer cells. Little is known, however, about the role of host cells on the sensitivity of cancer cells to receptor TKIs. We have therefore assessed the effect of crosstalk between stromal cells and lung cancer cells harboring EGFR mutations on susceptibility to EGFR-TKIs. Experimental Design: We evaluated the gefitinib sensitivity of lung cancer cells with EGFR-activating mutations, PC-9 and HCC827, when cocultured with fibroblasts and coinjected into severe combined immunodeficient mice. We also examined the effect of lung cancer cells to fibroblast recruitment. Results: Both human fibroblast cell lines and primary cultured fibroblasts produced various levels of hepatocyte growth factor (HGF). Lung cancer cells markedly recruited fibroblasts. The lung cancer cells became resistant to EGFR-TKIs when cocultured in vitro with HGF-producing fibroblasts and coinjected into severe combined immunodeficient mice. Importantly, combined use of gefitinib plus anti-HGF antibody or the HGF antagonist, NK4, successfully overcame the fibroblast-induced EGFR-TKI resistance both in vitro and in vivo. Colocalization of fibroblasts and HGF was detected in both xenograft tumors in mouse model and lung cancer patient specimens. Conclusions: These findings indicate that crosstalk to stromal fibroblasts plays a critical role in lung cancer resistance to EGFR-TKIs and may be an ideal therapeutic target in lung cancer with EGFR-activating mutations. ( Lung cancer is the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) accounting for ∼80% of lung cancers. The median survival of patients with metastatic NSCLC treated with the most active combination of conventional chemotherapy agents is 8 to 10 months (1, 2). Therefore, recent therapeutic strategies for NSCLC have focused on the development of molecular targeted agents.Epidermal growth factor receptor (EGFR), a member of a family of closely related growth factor receptor tyrosine kinases, is expressed in a majority of NSCLCs and has been an attractive target for the development of therapeutic agents. Almost 90% of these somatic activating mutations in EGFR consist of inframe deletions in exon 19 and L858R point mutations in exon 21 (3, 4). These mutations induce oncogenic activity and are closely correlated with sensitivity to small-molecule EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib. These mutations are more frequently present in females than in males, in nonsmokers than in smokers, in East Asians than in other ethnic groups, and in adenocarcinomas than in other tumor types (5). Several prospective clinical trials have shown that 70% to 75% of patients with tumors harboring these mu...

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“…The notion that the pronounced desmoplastic reaction in PDA actively contributes to the unusual refractoriness of PDA to systemic therapies has stimulated this area of research and revealed candidate therapeutic targets. Nonetheless, a potential role for desmoplasia in drug resistance has been only partially addressed, due to the multitude of signaling interactions between tumor cells and the surrounding microenvironment (37)(38)(39)(40).…”

Tumor‐associated macrophages correlate with response to epidermal growth factor receptor‐tyrosine kinase inhibitors in advanced non‐small cell lung cancer

“…Using in vitro and animal models, Wang et al previously demonstrated that crosstalk to stromal fibroblasts via hepatocyte growth factor (HGF) induces resistance of NSCLC to EGFR-TKIs. 24 Interestingly, serum HGF has been strongly related to the outcome of EGFR-TKI treatment. 25 TAMs may participate in EGFR-TKI resistance by supporting the formation and function of fibroblasts in the stroma.…”

Molecular pathology of lung cancer: key to personalized medicine

“…Despite impressive initial clinical responses, patients with EGFR-mutated adenocarcinomas almost inevitably develop drug resistance after B1 year of TKI treatment. 185,186 Studies have revealed several molecular mechanisms that may contribute to the development of tumor resistance to TKI therapy, 71,84,186,187 including acquired secondary EGFR mutation, activation of alternative signaling pathways that bypass the EGFR pathway, overexpression of HGF, 122 tyrosine protein kinase MET amplification, 53,124 epigenetic factors, 188 constitutive activation of signaling pathways downstream of EGFR, 13,189 tumor stromal and extracellular matrix alterations, 190,191 or host-related mechanisms such as rapid drug inactivation and ATP-binding cassette transporters efflux. 192 …”