Combined Effect of Hadron Therapy and PCSK9 Inhibition Therapy on the Immune Response in STK11-Deficient Lung Adenocarcinoma
4 affiliations
- 1Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow 117198, Russia
- 2Petrovsky Russian Scientific Center of Surgery (RSCS), 3 Tsurupa Street, Moscow 117418, Russia
- 3A.Tsyb Medical Radiological Research Center (MRRC), Federal State Budgetary Institution “National Medical Research Radiological Centre”, Ministry of Health of the Russian Federation, 4 Koroleva Str., Obninsk, Kaluga Region 249036, Russia
- 4Department of Oncology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Rd, 15 Shanghai 201399, China
Abstract
Lung cancer is the most common type of cancer worldwide. Tumors carrying a mutation in the STK11 gene are associated with severe prognosis and resistance to therapy. New treatments for pulmonary adenocarcinoma highlight the efficacy of High-LET neutron therapy, often combined with drug therapy. PCSK9, whose inhibitors are used to treat dyslipidemia, may also be a new target in lung cancer therapy. CRISPR-Cas9-mediated STK11 mutation was performed in murine LLC1 lung adenocarcinoma cells. Human A549 cells that naturally carry a homozygous loss-of-function mutation in the STK11 gene were also used. Cells were irradiated with protons, neutrons, and photons (2 Gy) and analyzed for survival, apoptosis, clonogenic survival assay, and evolocumab (PCSK9 inhibitor) sensitivity. In vivo xenograft (Nude) and syngeneic (C57BL/6) subcutaneous tumor models were neutron-irradiated (5 Gy). Tumor cell proliferation, microenvironment, and protein expression were assessed. High-LET irradiation confirmed the STK11-deficient lines radio resistance, which did not reduce under PCSK9 inhibitor treatment conditions in vitro. In animal models, the PCSK9 inhibitor decreased Ki67 index of tumor cells and infiltration of cancer-associated fibroblasts and macrophages in the combination therapy group. Particle therapy resistance serves as a crucial prognostic marker in the management of lung adenocarcinoma. Using cell lines and animal models, we successfully described this resistance phenotype and demonstrated the promising use of a PCSK9 inhibitor to enhance the efficacy of hadron radiotherapy against lung cancer.
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BibTeX
@article{gantsova2026combined,
title = {{Combined Effect of Hadron Therapy and PCSK9 Inhibition Therapy on the Immune Response in STK11-Deficient Lung Adenocarcinoma}},
author = {Elena Gantsova and Irina Arutyunyan and Anna Soboleva and Viktoriia Mikhailovskaia and Evgeniya Kananykhina and Daria Artemova and Kirill Mironov and Polina Vishnyakova and Andrey Elchaninov and Xuhui Bao and Andrey Makarov and Konstantin Gordon and Timur Fatkhudinov},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219778},
url = {https://www.mdpi.com/1422-0067/27/21/9778},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Combined Effect of Hadron Therapy and PCSK9 Inhibition Therapy on the Immune Response in STK11-Deficient Lung Adenocarcinoma
AU - Elena Gantsova
AU - Irina Arutyunyan
AU - Anna Soboleva
AU - Viktoriia Mikhailovskaia
AU - Evgeniya Kananykhina
AU - Daria Artemova
AU - Kirill Mironov
AU - Polina Vishnyakova
AU - Andrey Elchaninov
AU - Xuhui Bao
AU - Andrey Makarov
AU - Konstantin Gordon
AU - Timur Fatkhudinov
PY - 2026
DA - 2026/10/30
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219778
UR - https://www.mdpi.com/1422-0067/27/21/9778
AB - Lung cancer is the most common type of cancer worldwide. Tumors carrying a mutation in the STK11 gene are associated with severe prognosis and resistance to therapy. New treatments for pulmonary adenocarcinoma highlight the efficacy of High-LET neutron therapy, often combined with drug therapy. PCSK9, whose inhibitors are used to treat dyslipidemia, may also be a new target in lung cancer therapy. CRISPR-Cas9-mediated STK11 mutation was performed in murine LLC1 lung adenocarcinoma cells. Human A549 cells that naturally carry a homozygous loss-of-function mutation in the STK11 gene were also used. Cells were irradiated with protons, neutrons, and photons (2 Gy) and analyzed for survival, apoptosis, clonogenic survival assay, and evolocumab (PCSK9 inhibitor) sensitivity. In vivo xenograft (Nude) and syngeneic (C57BL/6) subcutaneous tumor models were neutron-irradiated (5 Gy). Tumor cell proliferation, microenvironment, and protein expression were assessed. High-LET irradiation confirmed the STK11-deficient lines radio resistance, which did not reduce under PCSK9 inhibitor treatment conditions in vitro. In animal models, the PCSK9 inhibitor decreased Ki67 index of tumor cells and infiltration of cancer-associated fibroblasts and macrophages in the combination therapy group. Particle therapy resistance serves as a crucial prognostic marker in the management of lung adenocarcinoma. Using cell lines and animal models, we successfully described this resistance phenotype and demonstrated the promising use of a PCSK9 inhibitor to enhance the efficacy of hadron radiotherapy against lung cancer.
SN - 1422-0067
ER -