Midkine May Play Key Role in SCLC

The growth factor midkine appears to promote cell proliferation and hinder the efficacy of cisplatin in patients with small cell lung cancer (SCLC), according to a new report.¹

The findings, which were published in Cancer Medicine, bolster the case that midkine may be a meaningful therapeutic target in SCLC and possibly other cancer types.

The findings suggest that inhibition of midkine might be a meaningful tool to improve treatment outcomes in SCLC. | Image credit: Pixel-Shot - stock.adobe.com

SCLC makes up a minority of lung cancer cases, but patients who are diagnosed with the disease tend to have poor outcomes, noted corresponding author Jun Sakakibara-Konishi, MD, PhD, of Hokkaido University, in Japan, and colleagues. According to data from the National Cancer Institute, just 9% of patients with SCLC survive 5 years.² One reason for the poor survival rates is the inability of platinum-based chemotherapy regimens to spark lasting results. While most patients respond to therapy, patients frequently develop resistance, Sakakibara-Konishi and colleagues said.¹ The addition of anti-programmed death ligand 1 (PD-1) antibodies to platinum combination chemotherapies can improve survival, they noted, but the effects are short-term in most patients.

The investigators in the new study decided to look at the heparin-binding growth factor midkine because it has already been shown to be expressed at high levels in a number of malignancies, and it has been found to contribute to cell proliferation, apoptosis evasion, and in the tumor microenvironment. Moreover, research into midkine’s role in other types of cancer suggests it can mediate therapeutic resistance.³ There has been relatively little research into the role of midkine in SCLC, specifically, Sakakibara-Konishi and colleagues said.¹

The investigators used a number of methods to assess the expression and role of midkine in SCLC. They analyzed midkine expression both in vitro and in vivo, using enzyme-linked immunosorbent assays (ELISA), immunochemistry, western blotting, and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assays.

Comparing 45 treatment-naive patients with SCLC with 10 healthy controls, they found that patients with SCLC had significantly higher levels of serum midkine. They then stratified patients with SCLC into a midkine-low and midkine-high group based on their serum midkine levels. They found no significant differences in patient characteristics between the 2 groups. However, they also found a trend toward a better prognosis in the group with lower levels of serum midkine. They found that serum midkine levels were associated with tumor burden. It may be possible to use midkine levels to help diagnose SCLC—a meaningful possibility given that the disease is most often diagnosed at an advanced stage.

“Furthermore, we found that s-MDK (serum midkine) levels were detected before disease progression as determined based on imaging and the analysis of tumor markers, indicating that it could serve as a predictive factor for disease progression during treatment,” they noted.

Previous research has indicated that midkine mediates cancer cell proliferation, survival, migration, and chemotherapeutic resistance. In this study, Sakakibara-Konishi and colleagues found that midkine activates the AKT pathway, though, in contrast to previous research, they said midkine’s connection to the MAPK pathway was less clear.

The investigators did not find a correlation between SCLC subtypes and midkine expression levels, though they said their study alone is insufficient to completely rule out the possibility. They also cautioned that they did not investigate the interplay between midkine and immune checkpoint inhibitors, which is a common therapeutic strategy in combination with chemotherapy.

The authors said their findings suggest that inhibition of midkine might be a meaningful tool to improve treatment outcomes in SCLC, benefitting the efficacy of both platinum-based chemotherapy and potentially immune checkpoint inhibitors.

References

1. Ito S, Sakakibara-Konishi J, Sato M, et al. Midkine Promotes Tumor Growth and Attenuates the Effect of Cisplatin in Small Cell Lung Cancer. Cancer Med. 2025;14(13):e71034. doi:10.1002/cam4.71034
2. American Cancer Society. 5-Year Survival Rates for Lung Cancer. American Cancer Society. Updated June 27, 2025. Accessed July 10, 2025. https://www.cancer.org/cancer/types/lung-cancer/detection-diagnosis-staging/survival-rates.html.
3. Yang KD, Wang Y, Zhang F, et al. CAF-derived midkine promotes EMT and cisplatin resistance by upregulating lncRNA ST7-AS1 in gastric cancer. Mol Cell Biochem. 2022;477(11):2493-2505. doi:10.1007/s11010-022-04436-x