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Cancer Sci. 2018 Apr 27. doi: 10.1111/cas.13624. [Epub ahead of print]

Collagen type I induces EGFR-TKI resistance in EGFR-mutated cancer cells via mTOR activation through Akt-independent pathway.

Author information

1
Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
2
Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
3
Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
4
Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
5
Division of Genome Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
6
Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
7
Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.

Abstract

Primary resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a serious problem in lung adenocarcinoma patients harboring EGFR mutations. The aim of this study was to examine whether and how collagen type I (Col I), the most abundantly deposited matrix in tumor stroma, affects EGFR-TKI sensitivity in EGFR mutant cells. We evaluated the EGFR-TKI sensitivity of EGFR mutated cancer cells cultured with Col I. Changes in the activation of downstream signaling molecules of EGFR were analyzed. We also examined the association between the Col I expression in tumor stroma in surgical specimens and EGFR-TKI response of postoperative recurrence patients with EGFR mutations.Compared to cancer cells without Col I, survival rate of cancer cells cultured with Col I was significantly higher after EGFR-TKI treatment. In cancer cells cultured with and without Col I, EGFR-TKI suppressed the levels of p-EGFR, p-ERK1/2, and p-Akt. When compared to cancer cells without Col I, expression of p-P70S6K, a hallmark of mTOR activation, was dramatically upregulated in cancer cells with Col I. This activation was maintained even after EGFR-TKI treatment. Simultaneous administration of EGFR-TKI and mTOR inhibitor abrogated Col I-induced resistance to EGFR-TKI. Patients with Col I-rich stroma had a significantly shorter progression-free survival time after EGFR-TKI therapy (238 days vs 404 days; P < 0.05).Col I induces mTOR activation through Akt-independent pathway, which results in EGFR-TKI resistance. Combination therapy using EGFR-TKI and mTOR inhibitor could be a possible strategy to combat this resistance. This article is protected by copyright. All rights reserved.

KEYWORDS:

mTOR ; Collagen type I; EGFR-TKI; EGFR-activating mutation; Lung adenocarcinoma

PMID:
29701925
DOI:
10.1111/cas.13624
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