Biomarker LEPRE1 induces pelitinib-specific drug responsiveness by regulating ABCG2 expression and tumor transition states in human leukemia and lung cancer

A-Ram Lee,Joungsun Jung,Jee Yoon Shin,Ji-Young Kim,Sunho Lee,Kyoung-Sik Moon

doi:10.1038/s41598-022-06621-w

Abstract

Biomarkers for treatment sensitivity or drug resistance used in precision medicine include prognostic and predictive molecules, critical factors in selecting appropriate treatment protocols and improving survival rates. However, identification of accurate biomarkers remain challenging due to the high risk of false-positive findings and lack of functional validation results for each biomarker. Here, we discovered a mechanical correlation between leucine proline-enriched proteoglycan 1 (LEPRE1) and pelitinib drug sensitivity using in silico statistical methods and confirmed the correlation in acute myeloid leukemia (AML) and A549 lung cancer cells. We determined that high LEPRE1 levels induce protein kinase B activation, overexpression of ATP-binding cassette superfamily G member 2 (ABCG2) and E-cadherin, and cell colonization, resulting in a cancer stem cell-like phenotype. Sensitivity to pelitinib increases in LEPRE1-overexpressing cells due to the reversing effect of ABCG2 upregulation. LEPRE1 silencing induces pelitinib resistance and promotes epithelial-to-mesenchymal transition through actin rearrangement via a series of Src/ERK/cofilin cascades. The in silico results identified a mechanistic relationship between LEPRE1 and pelitinib drug sensitivity, confirmed in two cancer types. This study demonstrates the potential of LEPRE1 as a biomarker in cancer through in-silico prediction and in vitro experiments supporting the clinical development of personalized medicine strategies based on bioinformatics findings.

Highlights

According to the United States National Institutes of Health (NIH), precision medicine is “an emerging approach for disease treatment and prevention accounting for individual variability in genes, environment, and lifestyle”[1]
We investigated pelitinib sensitivity and determined the expression of Leucine-proline-enriched proteoglycan 1 (LEPRE1) in acute myeloid leukemia (AML) cell lines and lung cancer cell line A549, referring to biomechanical information derived from in-silico analyses
We found that LEPRE1 or CCRL2 overexpression was associated with pelitinib sensitivity, and TAX1BP3 overexpression was associated with afatinib sensitivity (Fig. 1a)

Summary

Introduction

According to the United States National Institutes of Health (NIH), precision medicine is “an emerging approach for disease treatment and prevention accounting for individual variability in genes, environment, and lifestyle”[1]. EGFR signaling overactivation has been detected in various malignant tumors, including non-small cell lung cancer (NSCLC), colon, head and neck, breast, and ovarian cancer[16,17,18]. For this reason, EGFR activation and subsequent intracellular signaling molecules have long been attractive candidates as anticancer drug t argets[19]. There are currently three generations of EGFR tyrosine kinase inhibitors (TKIs), namely, first-generation agents erlotinib and gefitinib, the second-generation ErbB family blocker afatinib, and pelitinib (EKB-569), and third-generation osimertinib[20]. The second-generation EGFR-TKI pelitinib is a potent, low-molecular-weight, selective, irreversibly binding inhibitor of EGFR TK a ctivity[21]. In contrast to other EGFR-TKIs, pelitinib targets upstream molecules, such as EGFR signaling and HER-2, and downstream components such as Src, MEK/ERK, and Raf[22,23]

Methods

Results

Conclusion