@PhdThesis{duepublico_mods_00075256,
  author = 	{Ho, Cassandra Su Lyn},
  title = 	{Mechanisms of resistance to targeted therapy in non-small cell lung cancer: Strategies for modeling and combating acquired resistance},
  year = 	{2021},
  month = 	{Dec},
  day = 	{22},
  abstract = 	{Lung cancer remains the leading cause of cancer-related deaths worldwide; non-small cell lung cancer (NSCLC) accounts for 84{\%} of all lung cancers, with most patients having advanced disease at the time of diagnosis. Identification of targetable alterations such as anaplastic lymphoma kinase (ALK) and Kirsten rat sarcoma virus (KRAS) has revolutionized treatment of patients with advanced NSCLC but acquired drug resistance represents a major challenge in achieving long-term remission. Hence, further studies identifying mechanisms underlying resistance and strategies to overcome resistance are imperative to improve patient outcomes. Herein, patient-derived echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene and KRAS p.G12C models were successfully developed both in vitro and in vivo; representing two patient groups that are eligible for targeted therapies and account for approximately 5{\%} and 35{\%} of NSCLC, respectively. Sequencing of grafted tumors from ALK-positive lung cancers exhibited conservation of molecular features of their original patient tumors. They were shown to be promising modalities for better understanding of patient response to therapy and evolution of tumor resistance. Thus, these types of models and drug-resistant variants derived thereof could be valuable in guiding clinical treatment decisions. Additionally, in this thesis, elevated expression of human epidermal growth factor receptor 2 (HER2) was revealed to be a mediator of clinical resistance to KRAS G12C inhibition. This upregulation resulted in extracellular signal-regulated kinase 1/2 (ERK1/2) signaling-dependent resistance to sotorasib, a KRAS p.G12C inhibitor. Importantly, co-targeting KRAS G12C and Src homology region 2-containing protein tyrosine phosphatase (SHP2) restored suppression of the ERK1/2 signaling pathway and ERK-dependent genes. This was further validated by growth inhibition of KRAS p.G12C-mutant tumors with and without elevated HER2 expression in vivo, corroborating the idea that co-treatment could be utilized both as preventive and curative modalities. Further development on our established patient-derived KRAS p.G12C model would also be highly beneficial in studies of clinical resistance. Overall, the findings presented here offer a promising strategy to tackle off-target resistance to KRAS G12C inhibitors, therefore closing a gap in the rapidly evolving field of KRAS targeting drugs in clinical development.},
  doi = 	{10.17185/duepublico/75256},
  url = 	{https://duepublico2.uni-due.de/receive/duepublico_mods_00075256},
  url = 	{https://doi.org/10.17185/duepublico/75256},
  file = 	{:https://duepublico2.uni-due.de/servlets/MCRFileNodeServlet/duepublico_derivate_00074978/Diss_Cassandra_Ho.pdf:PDF},
  language = 	{en}
}