Whole genome doubling (WGD) is a frequent and early event in tumorigenesis linked to poor prognosis. WGD leads to chromosomal instability and aneuploidies, driving intratumor heterogeneity and tumour evolution. Despite its role in cancer progression, our understanding of WGD’s impact is limited. Recent studies suggest some predictability in tumour evolution following WGD. However, studying tumour evolution in patients requires frequent sampling, which is unethical and impractical. To address these limitations, this project employs a prospective cell line model. Using lineage tracing and single-cell sequencing, we will create human cellular models to analyse clonal evolution and identify aneuploidies with disease-driving capacity. We will then pinpoint actionable targets within these aneuploidies to discover vulnerabilities and viable drug targets, aiming to improve treatment outcomes in advanced cancer. The outcomes of this research will have significant implications for molecular biology and precision medicine, providing valuable insights into cancer development and heterogeneity. This work may refine cancer classification and future treatments.