A Protein Biomarker Aids Cancer Patients by Controlling the Dosage of Highly Toxic Cisplatin

A team of Japanese investigators has identified a protein biomarker that may help clinicians control the dosage of the highly toxic chemotherapeutic drug cisplatin.

While cisplatin (CDDP) is effective in many types of cancers - including testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain tumors, and neuroblastoma - in high doses it causes cytotoxic effects that may worsen patients’ condition. Thus, a marker of sensitivity to CDDP is necessary to enhance the safety and efficiency of CDDP administration.

In this regard, investigators at Niigata University (Japan) and their collaborators focused on the protein adipose most abundant 2 (APM2) to examine its potential as a marker of CDDP sensitivity. The relationship of APM2 expression with the mechanisms of CDDP resistance was examined in vitro and in vivo using hepatocellular carcinoma (HCC) cells, tissues, and serum from71 HCC patients treated initially with intrahepatic arterial infusion of CDDP followed by surgical resection. The predictability of serum APM2 for CDDP sensitivity was assessed in an additional 54 HCC patients and 14 gastric cancer (GC) patients.

Results revealed that APM2 expression in CDDP-resistant HCC was significantly higher both in serum and the tissue. Bioinformatic analyses and histological analyses demonstrated upregulation of the ERCC6L (DNA excision repair protein ERCC6-like) gene by APM2, which was thought to account for the degree of APM2 expression.

Serum APM2 levels and chemosensitivity for CDDP were assessed, and the cut-off value of serum APM2 for predicting the sensitivity to CDDP was determined to be 18.7 micrograms/milliliter. This protein concentration was evaluated in 54 HCC and 14 GC patients for its predictability of CDDP sensitivity, resulting in predictive value of 77.3% and 100%, respectively.

"Our results demonstrate a significant relationship between the high level of APM2 expression in serum, cancerous cells in the liver, the surrounding liver tissue, and cisplatin resistance. The study reveals that APM2 expression is related to cisplatin sensitivity," said first author Dr. Kenya Kamimura, lecturer in the division of gastroenterology and hepatology at Niigata University. "The serum APM2 can be an effective biomarker of the liver and gastric cancer cells for determining the sensitivity to cisplatin. The results of the study would provide an advantage for the technicians, allowing easy adaption in small local clinics."

Dr. Kamimura said, "To the best of our knowledge, this is the first report to demonstrate that the serum level of APM2 can be the predictor of the CDDP chemosensitivity. This study thus represents a milestone for detecting CDDP sensitivity, and further studies will help modify APM2 expression, which could contribute to the chemosensitization of the tumor."

The cisplatin resistance study was published in the March 18, 2021, online edition of the journal Scientific Reports.

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