Advancing precision oncology: insights from C-terminal FGFR2/3 truncations and MYC-driven mTOR inhibitor resistance

Abstract

Precision oncology aims to deliver the right drug(s) to the right patient at the right time. A major challenge is that many genetic alterations identified through tumor profiling remain functionally uncharacterized and are classified as “variants of unknown significance” (VUS), meaning it is unclear whether they contribute to cancer development or treatment response. Distinguishing cancer-driving alterations from neutral changes is essential, particularly in cancer genes with available targeted therapies. This thesis advances our understanding of genomic alterations in the fibroblast growth factor receptor (FGFR) family and elucidates mechanisms of therapeutic resistance to drugs targeting the PI3K-AKT-mTOR pathway. By integrating large-scale analyses of human tumors with in vitro assays and somatic in vivo tumor modeling, this work identifies previously underappreciated alterations affecting the C-terminal tail of FGFR2 and FGFR3 as a clinically relevant class of cancer-driving events sensitive to FGFR-targeted treatment. These findings support reclassifying numerous FGFR alterations previously considered VUS as clinically actionable, potentially expanding the number of patients who may benefit from FGFR-targeted therapies. Beyond FGFR biology, this thesis identifies MYC activation as a key driver of mTOR inhibitor resistance in breast cancer by sustaining protein synthesis and tumor growth, highlighting its potential as a biomarker and therapeutic target.