American Association for Cancer Research
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Supplemental Tables 1-4 from Podoplanin-Positive Cancer-Associated Fibroblasts in the Tumor Microenvironment Induce Primary Resistance to EGFR-TKIs in Lung Adenocarcinoma with EGFR Mutation

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posted on 2023-03-31, 18:10 authored by Tatsuya Yoshida, Genichiro Ishii, Koichi Goto, Shinya Neri, Hiroko Hashimoto, Kiyotaka Yoh, Seiji Niho, Shigeki Umemura, Shingo Matsumoto, Hironobu Ohmatsu, Shinsuke Iida, Akio Niimi, Kanji Nagai, Yuichiro Ohe, Atsushi Ochiai

Supplemental Tables 1-4. Supplemental Table 1: Characteristics of primary adenocarcinoma from which CAFs were obtained. Supplemental Table 2: Primary tumor characteristics(N=106). Supplemental Table 3: Impact of predictive factors on progression free survival of EGFR-TKI in patients with EGFR activating mutation by univariate and multivariate analysis (n=106). Supplemental Table 4: The correlation between PDPN expression status and clinical response to EGFR-TKIs in patients with EGFR common mutations, exon 19 deletion and L858R (N=102).

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ARTICLE ABSTRACT

Purpose: The biologic characteristics of microenvironmental constituents, especially cancer-associated fibroblasts (CAF), can be key regulators of the cellular sensitivity to molecular-targeted therapy. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have marked therapeutic effects against non–small cell lung cancer (NSCLC) with EGFR mutations, but some patients have exhibited primary resistance to EGFR-TKIs. We recently reported that podoplanin-positive fibroblasts are associated with a tumor-promoting phenotype of CAFs in lung adenocarcinoma. The aim of this study was to evaluate whether the susceptibility of NSCLC to EGFR-TKIs could be affected by podoplanin-expressing CAFs.Experimental Design: We evaluated the EGFR-TKI sensitivity of EGFR-mutant lung adenocarcinoma cell lines cocultured with podoplanin-expressing CAFs. We also examined the association between the expression of podoplanin in CAFs in surgical specimens and EGFR-TKI response of postoperative recurrent patients with EGFR mutations (N = 106).Results: Lung adenocarcinoma cell lines became more resistant to EGFR-TKI when cocultured with podoplanin-expressing CAFs, compared with control CAFs in vitro. The knockdown of podoplanin expression on CAFs cancelled the resistance to EGFR-TKIs in cancer cells. Compared with control CAFs, the cancer cells that were cocultured with podoplanin-positive CAFs continued to exhibit significantly higher p-ERK levels after treatment with gefitinib. Furthermore, postoperative recurrent patients with podoplanin-positive CAFs had a significantly lower overall response rate to EGFR-TKIs compared with those with podoplanin-negative CAFs (53% vs. 83%; P < 0.01).Conclusions: Podoplanin-positive CAFs play an important role in primary resistance to EGFR-TKIs and may be an ideal therapeutic target for use in combination therapy with EGFR-TKIs. Clin Cancer Res; 21(3); 642–51. ©2014 AACR.

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