In silico study of Actinium-225 (225AC) labelled pentixafor targeting CXCR4 and genetic dependency for breast cancer therapy

The development of breast cancer treatment methods is currently growing rapidly with the emergence of the era of targeted therapy. Various methods of breast cancer treatment by targeting certain receptors that are specific to cancer cells continue to be developed, one of which is by utilising the radioisotope Actinium-225 (225Ac). As an alpha particle-emitting isotope, 225Ac is known to have enormous potential for cancer therapy. One potential target receptor is C-X-C chemokine receptor type 4 (CXCR4), a small molecule chemoattractive cytokine that regulates many cellular functions associated with tumour dissemination and prognosis, including breast cancer. This study aimed to assess the suitability of 225Ac-Pentixafor for breast cancer treatment by determining the expression of CXCR4 in several breast cancer cell lines, optimised 225Ac-Pentixafor structure and calculating the binding potential of Actinium-225 labelled with pentixafor, one of the most advanced high-affinity ligand targeting CXCR4. In this study, the genetic dependency of CXCR4 on breast cancer cell lines was determined using Depmap R-Packages, 225Ac-Pentixafor structure was optimised using density functional theory (DFT) method with triple zeta potential (TZP) basis set running in Orca software, and docking study was carried out using Autodock 4. According to the findings of the in silico study, CXCR4 is highly expressed in blood cells, lymphocytes, and plasma cells. In solid tumours such as breast cancer, it is known that the genetic dependency in the transcript per million (TPM) based on 22Q2 expression is cell line DU4475 (6.833). Several cell lines that are often used in breast cancer research also have high CXCR4 expressions, such as MCF7 (5.462) and MDA-MB-361 (5.562). Additionally, the total energy of optimised 225Ac-Pentixafor was -24,597 kcal.mol−1, whereas the estimated free energy of 225Ac-Pentixafor binding with CXCR4 was -11.72 kcal.mol−1. This energy value indicates that 225Ac-Pentixafor is stable, and binding with CXCR4 is favourable. These findings have important implications for the potential use of 225Ac-Pentixafor in breast cancer therapy and several cell lines with high CXCR4 expression that can be used for in vitro studies.