Collagen type I induces EGFR‐TKI resistance in EGFR‐mutated cancer cells by mTOR activation through Akt‐independent pathway

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, the 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 phosphorylated (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 treatment with 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 < .05). Collagen type I induces mTOR activation through an 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.

The role of collagen in cancer: from bench to bedside

“…In addition, increased COLI did not alter primary tumor growth and ERα expression but enhanced circulating cancer cells and metastasizing cancer cells with decreased phospho-STAT5 expression, increased phospho-ERK1/2, and increased phospho-AKT expression; this phenomenon coincided with the formation of invasive protrusions of the primary tumor harboring collagen fibers angled perpendicularly to the tumor mass [75]. However, COLI in non-small cell lung cancer (NSCLC) induced mTOR activation through an AKT-independent pathway, leading to EGFR-tyrosine kinase inhibitor resistance [76]. The Notch3-COL4A2 loop promoted anoikis resistance with a reduction in phosphorylated AKT and ERK 1/2 in ovarian cancer cells [77].…”

Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion

“…However, PD-(L)1 blockade in KP GEM mice showed only transient effects, without a long-term reduction in primary lung tumor growth or improvement in animal survival 8 . In addition to high PD-L1 expression, our prior work also demonstrated that KP lung tumors have increased LOXL2 crosslinking, which stabilizes and enhances the deposition of collagen, a main component of the ECM that has been implicated in promoting lung tumor progression, metastasis and drug resistance [14][15][16][17] . Furthermore, studies have also correlated TGF-β signaling and TGF-βassociated ECM gene signatures, such as collagen, with tumor immune suppression and anti-PD-1/PD-L1 resistance 18,19 .…”

Extracellular matrix alterations in low‐grade lung adenocarcinoma compared with normal lung tissue by imaging mass spectrometry

“…In nonsmall cell lung cancer, high stroma‐tumor ratios (≥50% stroma) correlate with decreased survival . Culture of cells from LUAD diagnosed patients showed that the presence of collagen type 1, a main protein deposited in fibrosis, resulted in significantly shorter progression‐free survival time after therapy . Since cancer‐related mortality is due to tumor cell metastasis, which is driven by tumor‐associated fibroblasts and fibrosis, approaches to mitigate fibrotic initiation in the setting of solid tumors could reduce metastasis and improve survival.…”