PIM kinase inhibition counters resistance to radiotherapy and chemotherapy in human prostate cancer

IF 4.9 1区医学 Q1 ONCOLOGY

Radiotherapy and Oncology Pub Date : 2025-02-18 DOI:10.1016/j.radonc.2025.110794

Anne Rajkumar-Calkins , Vinay Sagar , Jian Wang , Shania Bailey , Philip Anderson , Sarki A. Abdulkadir , Austin N. Kirschner

{"title":"PIM kinase inhibition counters resistance to radiotherapy and chemotherapy in human prostate cancer","authors":"Anne Rajkumar-Calkins , Vinay Sagar , Jian Wang , Shania Bailey , Philip Anderson , Sarki A. Abdulkadir , Austin N. Kirschner","doi":"10.1016/j.radonc.2025.110794","DOIUrl":null,"url":null,"abstract":"<div><h3>Purpose</h3><div>PIM kinases are associated with treatment resistance and poor prognosis in prostate cancer through roles in DNA damage response, cellular metabolism, proliferation, and survival. We hypothesized PIM inhibition addresses treatment resistance to radiotherapy and docetaxel in prostate cancer.</div></div><div><h3>Methods</h3><div>PIM inhibition in prostate cancer cell lines was examined by phosphorylated H2AX and colony formations assays. In normal and castrated mice with prostate tumor xenografts, tumor growth was monitored with daily oral PIM inhibition +/- fractionated radiotherapy (RT) or docetaxel. Radiotherapy was given 30 Gy in 15 treatments, mimicking clinical conventional daily treatment over 3 weeks in a translational murine model system.</div></div><div><h3>Results</h3><div>PIM inhibition decreased radiotherapy-induced DNA-damage repair and decreased cell proliferation and survival. In mice, PIM inhibition increased the efficacy of both radiation and docetaxel to reduce tumor size in hormone-dependent and −independent xenografts. Xenografts showed altered gene expression changes, including downregulation of ribosomal pathways and upregulation of cardiomyocyte signaling pathways, due to PIM inhibition as analyzed by RNA-Seq. Immunostaining of multiple proteins, including COX-2 and MDM2, was altered by PIM inhibition.</div></div><div><h3>Conclusions</h3><div>PIM inhibition addresses treatment resistance to docetaxel and radiotherapy in multiple prostate cancer models. Our data provide a strong rationale for testing PIM inhibitors in combination with standard therapies for treatment-resistant high-risk localized or metastatic prostate cancer in clinical trials.</div></div>","PeriodicalId":21041,"journal":{"name":"Radiotherapy and Oncology","volume":"206 ","pages":"Article 110794"},"PeriodicalIF":4.9000,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Radiotherapy and Oncology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0167814025000891","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose

PIM kinases are associated with treatment resistance and poor prognosis in prostate cancer through roles in DNA damage response, cellular metabolism, proliferation, and survival. We hypothesized PIM inhibition addresses treatment resistance to radiotherapy and docetaxel in prostate cancer.

Methods

PIM inhibition in prostate cancer cell lines was examined by phosphorylated H2AX and colony formations assays. In normal and castrated mice with prostate tumor xenografts, tumor growth was monitored with daily oral PIM inhibition +/- fractionated radiotherapy (RT) or docetaxel. Radiotherapy was given 30 Gy in 15 treatments, mimicking clinical conventional daily treatment over 3 weeks in a translational murine model system.

Results

PIM inhibition decreased radiotherapy-induced DNA-damage repair and decreased cell proliferation and survival. In mice, PIM inhibition increased the efficacy of both radiation and docetaxel to reduce tumor size in hormone-dependent and −independent xenografts. Xenografts showed altered gene expression changes, including downregulation of ribosomal pathways and upregulation of cardiomyocyte signaling pathways, due to PIM inhibition as analyzed by RNA-Seq. Immunostaining of multiple proteins, including COX-2 and MDM2, was altered by PIM inhibition.

Conclusions

PIM inhibition addresses treatment resistance to docetaxel and radiotherapy in multiple prostate cancer models. Our data provide a strong rationale for testing PIM inhibitors in combination with standard therapies for treatment-resistant high-risk localized or metastatic prostate cancer in clinical trials.

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Radiotherapy and Oncology 医学-核医学

CiteScore

10.30

自引率

10.50%

发文量

2445

审稿时长

45 days

期刊介绍： Radiotherapy and Oncology publishes papers describing original research as well as review articles. It covers areas of interest relating to radiation oncology. This includes: clinical radiotherapy, combined modality treatment, translational studies, epidemiological outcomes, imaging, dosimetry, and radiation therapy planning, experimental work in radiobiology, chemobiology, hyperthermia and tumour biology, as well as data science in radiation oncology and physics aspects relevant to oncology.Papers on more general aspects of interest to the radiation oncologist including chemotherapy, surgery and immunology are also published.