PTEN inactivation has distinct effects on the signalling properties of EGFR and MET and their response to kinase inhibitors

Receptor tyrosine kinases (RTKs) are a family of cell-surface receptors that play a major role in regulating pro-proliferative and pro-survival signalling pathways, such as the Phosphoinositide 3-kinase (PI3K/Akt) pathway. When aberrantly activated, RTKs can promote oncogene addiction, causing tumour cells to develop exquisite dependency on their activity. Consequently, various RTK inhibitors are approved for the targeted treatment of cancers with aberrant RTK activation. However, both de novo and acquired mechanisms of drug resistance pose challenges to such treatments. The loss of the tumour suppressor Phosphatase and Tensin Homolog (PTEN), a negative regulator of the PI3K/Akt pathway, is a common molecular dysfunction associated with resistance to inhibitors of Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2). Despite the irrefutable role of PTEN in tumorigenesis, our understanding of how PTEN regulates tyrosine kinase inhibitor (TKI) responses remains limited. This thesis investigates the molecular consequences of PTEN inactivation on EGFR and Mesenchymal to Epithelial Transition Receptor (MET) inhibitor responses, providing evidence that complete PTEN-inactivation is an RTK-selective mechanism of TKI resistance. As such, we find that PI3K/Akt pathway activation in relation to TKI resistance varies based on the identity of the driver RTK. Specifically, while MET-TKI resistance may be PI3K/Akt pathway-dependent, EGFR-TKI resistance to be at least partially PI3K/Akt-independent. We also provide some evidence that PTEN could modulate the abundance of certain RTK conformations, as well as affect receptor cellular localisation. Finally, through molecular profiling, new mediators of EGFR and MET inhibitor responses are identified. In particular, PIKfyve emerges as a potential therapeutic target in MET-driven cancers.