Negative feedback and oncogene signalling in leukaemia

Tyrosine kinase inhibitors (TKIs), used against cancer-promoting (oncogenic) tyrosine kinases, have created a new era of treatment for patients with leukaemia and solid tumours. Despite their clinical success in chronic myeloid leukaemia, TKI resistance is a common outcome in almost all other malignancies. Research has uncovered an unexpected dependence of tumour cells on negative feedback regulation of signalling pathways downstream of oncogenic tyrosine kinases. Professor Müschen aims to build a fundamental understanding of: why tyrosine-kinase-driven cancer cells are uniquely sensitive to loss of negative feedback; whether tyrosine-kinase-driven cancer cells can only thrive within the limits of a 'comfort zone' of oncogene signalling, with either attenuation (TKI) or hyperactivation (blockade of feedback) leading to cell death; and how ablation of negative feedback mechanistically leads to cell death. He then aims to leverage this information towards the development of a new therapy concept based on alternating treatment schedules between TKIs and inhibitors of feedback.