Combined Effect of Hadron Therapy and PCSK9 Inhibition Therapy on the Immune Response in STK11-Deficient Lung Adenocarcinoma

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.