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Lu, Cheng-Hsiang (Daniel)

University of British Columbia

The MET receptor is a critical mediator of tumour progression, frequently overexpressed in advanced lung adenocarcinomas. Despite the existence of clinically approved MET inhibitors, incorporating MET-targeted therapies seldom improve patient outcomes. Recent genome-wide sequencing efforts identified recurrent splice site mutations in the MET proto-oncogene, pointing to a novel role driving tumour initiation. Using matched RNA-seq analyses, these mutations were shown to produce MET mRNA lacking exon 14, which encodes the juxtamembrane regulatory domain responsible for c-CBL mediated receptor degradation. The detection of MET splicing mutations strongly predicts response to anti-MET targeted therapies, and a causal link is well-established. However, the molecular biology underpinning MET-dependent tumour initiation is less understood. In the era of MET-targeted therapies, elucidating these mechanisms is crucial, as response rates remain short of those achieved by other tyrosine kinase inhibitors (e.g. targeting EGFR or ALK), and the emergence of secondary resistance is predicted to limit long-term efficacy. In this thesis, I used expression profiling to identify transcriptional changes associated with MET splice-mutant tumours. I developed isogenic expression models to demonstrate that mutant MET preferentially engages the RAS/MAPK signaling pathway over parallel alternatives, suggesting a critical dependence that can be selectively targeted. In collaboration with clinical investigators, I confirmed the importance of this pathway by showing that KRAS alterations commonly emerge as a mechanism of resistance in patients receiving MET-targeted therapies. In parallel, I established anti-MET drug-resistant lines from MET-mutant cells, with the aim of uncovering additional alterations that might predict clinical resistance. Using targeted genomic sequencing, I discovered independent mutations in SPOP and MGA, both encoding negative regulators of MYC. Transcriptional profiling further support a mechanistic overlap whereby cells independently reactivate MYC to achieve resistance, subsequently validated through MYC overexpression and knockdown experiments. Finally, I established a murine model of mutant MET-driven lung cancer to demonstrate its in vivo transformative potential. I evaluated the utility of this model for elucidating mechanisms of MET-driven tumour initiation, and as a platform for testing treatment strategies. As a whole, this thesis explores the mechanistic bases of tumour initiation and drug resistance, representing a targeted effort at advancing MET treatment strategies.

Text

2023-07-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/85283

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/