Abstract C006: Fitness landscape modeling indicates decreased effectiveness of microtubule assembly targeting drugs in tumors demonstrating chromosomal instability (CIN)

Abstract Introduction: Tumor cells often display aberrant chromosome counts, or aneuploidy, which can be exacerbated by increased chromosome missegregation rates in a condition called chromosomal instability (CIN). Despite the prevalence of CIN in solid tumors and its correlation to poor patient prognosis, understanding how CIN status affects cancer aggression remains a contested issue. In this work, we present a novel mathematical model linking missegregation levels and degree of aneuploidy to the underlying fitness landscape, and examine how these fitness landscapes can affect drug efficacy. Methods: To model how chromosome counts can shift over time, we use a partial differential equation that contains a diffusion term corresponding to chromosome missegregation and a growth term proportional to the relative fitness of a particular chromosomal distribution. Using this framework, a fitness landscape that connects chromosome count to relative fitness can be inferred from a steady-state cellular population. Fluorescence in situ hybridization (FISH) was used to track chromosome counts in both CIN and non-CIN cell lines over the course of 2 months, with data collected for chromosome 10 individually and for the group of chromosomes 1, 5, and 19. Experimental results were then analyzed using our mathematical framework to determine fitness landscapes for both CIN and non-CIN cells. Results: A partial differential equation was developed to model how chromosome counts change over time based on a diffusion-like term corresponding to lagging chromosome rate and a growth rate based on a chromosome count’s contribution to overall cellular fitness. The CIN lines exhibited chromosome count distributions that were statistically closer to normal distributions than non-CIN lines. When connected to our mathematical model, these distributions imply that the CIN lines have a flatter fitness landscape than their non-CIN counterparts. This finding reinforces the notion that CIN lines are tolerant of highly varying degrees of aneuploidy. Conclusion: Our work suggests an underlying mechanism for the clinical observation that CIN tumors are more resilient to treatment with taxanes and other microtubule or mitotic targeting drugs. The flatter fitness landscapes associated with CIN provide an explanation for why these drugs are less effective, since increasing or decreasing the number of chromosomes in a CIN line does not lead to a relatively large change in fitness. Citation Format: Kelly Brock, Marianna Kleyman, Madison Stoddard, T. Ryan Gregory, Andrew Chen, Arijit Chakravarty. Fitness landscape modeling indicates decreased effectiveness of microtubule assembly targeting drugs in tumors demonstrating chromosomal instability (CIN) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C006.