This PhD thesis defence uses high-throughput CRISPR variant engineering to study how cancer mutations drive tumour behaviour. A prime-editing sensor enables efficient functional screening of ~1,000 TP53 patient variants, revealing effects missed by cDNA overexpression. Directed base-editing screens map resistance mutations across CDKs and drug modalities, predicting clinically relevant therapy response.

Cancer often becomes resistant to treatment due to the protein CDK8, which helps reprogram cancer cells. Traditional inhibitors fail because CDK8 still acts as a structural scaffold. This research develops targeted degraders that use the cell’s recycling system to eliminate CDK8 entirely, preventing resistance and improving future cancer therapies.

This research investigates how bacteria develop resistance to antibiotics, a growing global health threat. By identifying resistant bacteria and analysing how they chemically modify antibiotics, the work aims to uncover resistance mechanisms. These insights are essential for preserving antibiotic effectiveness and safeguarding treatments against life-threatening infections.

Fungal infections are becoming harder to treat as fungi rapidly evolve resistance to limited antifungal drugs. This research reveals that large, multi-gene mutations—once overlooked—are common in resistant fungi. Understanding these dramatic genetic changes is critical for developing more effective antifungal therapies.

Antibiotic resistance threatens to return medicine to a pre-antibiotic era. This research uses machine learning to study how bacteria balance resistance to antibiotics and bacteriophages. By revealing genetic trade-offs between attack and defense, the work enables smarter combination therapies that exploit bacterial weaknesses and prevent otherwise deadly infections.

Tuberculosis remains deadly despite relying on decades-old antibiotics. This research uses computational methods to identify immune response similarities between TB and other diseases, enabling drug repurposing. By borrowing already approved treatments, this approach aims to restore immune balance, combat drug resistance, and accelerate the development of new TB therapies.

Low-grade serous ovarian cancer frequently returns after standard treatment, and current targeted drugs eventually stop working. This research investigates why cancer cells become resistant, comparing them to prey that adapt to evade a predator. By treating patient-derived tumor cells with inhibitors and analyzing the genes activated in the resistant survivors, the research aims to uncover the mechanisms behind drug resistance and guide development of more effective therapies.

This research targets chronic lymphocytic leukemia relapse by focusing on Bruton’s Tyrosine Kinase (BTK), a key cancer-driving protein that often mutates and becomes drug-resistant. Using “molecular glues,” the project aims to degrade BTK—even when mutated—offering a new therapeutic strategy that could overcome resistance and improve outcomes for (chronic lymphocytic leukemia) CLL and other BTK-dependent cancers.

This research investigates a novel two-drug therapy for ovarian cancer that kills cancer cells without harming healthy tissues and partially reactivates the suppressed immune system. The PhD work explores how this immune “reawakening” occurs, aiming to identify new strategies to enhance it and create more effective, resistance-proof treatments.

This research investigates how Plasmodium falciparum invades human red blood cells. By focusing on the neglected role of red cell surface structures, it aims to uncover molecular interactions essential for invasion. Understanding these mechanisms may guide the development of new treatments for drug-resistant malaria, a disease killing a child every minute.