Genome instability associated with oncogene amplification and its therapeutic strategy

Sloan-Kettering Inst Can Research, New York NY

Investigators

Abstract

PROJECT SUMMARY Focal oncogene amplification (OA) is a common driver of cancer and is linked to early relapse, poor survival, and treatment resistance. Despite the success of anti-HER2 therapy in HER2-amplified breast cancers, targeting amplified oncogenes remains challenging in many cancer types. The molecular mechanisms underlying these aggressive clinical features are poorly understood, which hampers the development of effective therapies targeting OAs. Preliminary data reveal extensive intratumoral heterogeneity in cases with focal OA. The genomic rearrangements and subclonal copy-number alterations observed post-OA suggest that cancer cells follow divergent evolutionary paths, rather than proliferating uniformly. This may distinguish OA from other cancer driver events and explain the links to adverse clinical outcomes. The primary hypothesis of this proposal is that the mutational processes amplifying oncogenes induce genome instability through structural rearrangements, facilitating the evolution into therapy-resistant clones. This hypothesis will be tested in cohorts of patients with breast and lung cancers, where OAs are prevalent, clinically relevant, and develop through distinctive mechanisms. Single-cell whole-genome sequencing will be employed to detect cell-to-cell genomic variations and will be jointly analyzed with long-read sequencing and single-cell RNA sequencing. Specifically, the study will: 1) Differentiate the mechanisms by which OA leads to genome instability, distinguishing structural instability (causing genomic rearrangements) from phenotypic instability (overexpressed oncogenes causing mitotic errors) 2) Identify DNA repair pathways that enable OA-driven clonal evolution and their interactions with the cell cycle, and 3) Investigate the role of OA-associated genome instability in the development of therapy-resistant clones by leveraging a new cell-free DNA assay detecting subclone-specific genomic rearrangements. Furthermore, synthetic lethal strategies to prevent OA-driven clonal evolution before the emergence of therapy-resistant clones will be evaluated in lung cancer cell lines and patient-derived xenograft models. DNA double-strand break repair pathways will be tested as therapeutic targets to mitigate OA-associated genome instability and therapy resistance. These studies aim to provide insights into the mechanisms underlying adverse clinical outcomes associated with OAs and propose new therapeutic strategies for OA-driven cancers, addressing significant clinical needs. The applicant, Dr. June-Koo Lee, a Medical Oncology Fellow at Memorial Sloan Kettering Cancer Center (MSK), has outlined a five-year career plan under the mentorship of Drs. Sohrab Shah and Charles Rudin, experts in cancer evolution and lung cancer, respectively. Dr. Lee will develop expertise in 1) single-cell analyses, 2) plasma cell-free DNA assays, and 3) patient-derived xenograft experiments. His advisory committee will guide his training and research. MSK provides the ideal support for Dr. Lee to transition into an R01-funded tenure- track physician-scientist role, focusing on clonal evolution mechanisms and their clinical implications.