Two first in class anti-cancer drugs (PLK4i and TTKi) recently developed in the laboratory of Dr. Tak Mak have demonstrated promising abilities to potently inhibit tumour growth in breast cancer models, highlighting their potential as new therapeutic compounds that will positively impact the survival of breast cancer patients. Although a large fraction of breast cancers respond to these drugs, preclinical tests have also revealed that some breast tumours are resistant and others that are initially sensitive acquire resistance. Drug resistance is a major clinical hurdle in medical oncology that limits drug efficacy and consequently patient survival; therefore, to optimize the clinical development of PLK4i and TTKi in order to improve breast cancer patient response and outcome, I will study the mechanisms conferring breast tumour resistance to these compounds and how to overcome them. By comparing resistant and sensitive breast cancers, I will identify specific genes that mediate PLK4i and TTKi resistance. Once I identify these genes, I will develop strategies to inhibit them and combine these strategies with PLK4i/TTKi treatment to sensitize breast cancer cells to PLK4i/TTKi. These strategies could be translated to enhance patient response to PLK4i/TTKi in the clinic. My discoveries may lead to the development of clinical tests to predict whether or not breast cancer patients will respond to PLK4i or TTKi, and these tests could inform clinicians about which treatment strategy is most likely to benefit individual patients. The findings from this project have the potential to be rapidly integrated into the clinical management of patients and to ultimately improve breast cancer survival.