Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer

Abstract

Background Platinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue platinum concentration in NSCLC specimens was significantly associated with reduced tumor response. Furthermore, low expression of the copper transporter CTR1, a transporter of platinum uptake was associated with poor clinical outcome following platinum-based therapy in NSCLC patients. We investigated the relationship between tissue platinum concentrations and CTR1 expression in NSCLC specimens. Methods We identified paraffin-embedded NSCLC tissue blocks of known tissue platinum concentrations from 30 patients who underwent neoadjuvant platinum-based chemotherapy at MD Anderson Cancer Center. Expression of CTR1 in tumors and normal adjacent lung specimens was determined by immunohistochemistry with adequate controls. Results Tissue platinum concentration significantly correlated with tumor response in 30 patients who received neoadjuvant platinum-based chemotherapy (P<0.001). CTR1 was differentially expressed in NSCLC tumors. A subset of patients with undetectable CTR1 expression in their tumors had reduced platinum concentrations (P=0.058) and tumor response (P=0.016) compared to those with any level of CTR1 expression. We also observed that African Americans had significantly reduced CTR1 expression scores (P=0.001), tissue platinum concentrations (P=0.009) and tumor shrinkage (P=0.016) compared to Caucasians. Conclusions To our best knowledge this is the first study investigating the function of CTR1 in clinical specimens. CTR1 expression may be necessary for therapeutic efficacy of platinum drugs, consistent with previous preclinical studies. A prospective clinical trial is necessary to develop CTR1 into a potential biomarker for platinum drugs.

Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation

“…Multiple independent research groups in earlier reports identified that reduced intracellular drug accumulation rendered ovarian cancer, non‐small‐cell lung cancer, prostatic cancer, hepatoma cancer, cervical cancer, and colorectal cancer cell lines resistant to cDDP . Recent studies have provided further evidence of the association between cancer tissue platinum concentration and chemotherapy response in muscle‐invasive bladder cancer and non‐small‐cell lung cancer . This evidence suggests that reduced platinum accumulation is an important mechanism of platinum resistance.…”

Transcriptome analysis of copper homeostasis genes reveals coordinated upregulation of SLC31A1,SCO1, and COX11 in colorectal cancer

“…A correlation between higher hCTR1 levels and higher platinum drug uptake in tumor cells sensitive to the drug has been reported . The observation that CTR1 expression is upregulated at similar levels in MSI and MSS tumors would suggest a sensitivity of both types of CRC to platinum drugs.…”

“…More recently Kim et al . could detect the expression of CTR1 by immunohistochemistry in several samples of nonsmall cell lung cancer and corresponding normal epithelium.…”

NEAT1 upregulates EGCG-induced CTR1 to enhance cisplatin sensitivity in lung cancer cells

“…As the primary copper influx transporter, CTR1 controls cellular cDDP accumulation. The correlation between higher CTR1 levels and higher platinum drug uptake in tumor cells has been confirmed in a number of studies [9, 12]. CTR1 upregulation can sensitize tumor cells to platinum drugs, while CTR1 downregulation promotes resistance [9].…”