Integrated Drug Response Profiling of Myelofibrosis Patients

Myelofibrosis (MF) is a chronic blood cancer characterized by scarring of the bone marrow. Molecularly, the disease is driven by mutations occurring in hematopoietic stem and progenitor cells (HSPCs). Strikingly, mutations underlying myelofibrosis are less heterogeneous than in other cancers: in >90% of the patients, disease is driven by mutations in either the JAK2 or Calreticulin (CALR) gene.

In this study, Wildschut et al. used a microscopy-​based drug response profiling technique (pharmacoscopy) to screen drugs readily approved for clinical use in other diseases for efficacy in MF patients. More specifically, blood collected from a cohort of MF patients was screened for drugs able to kill mutated HSPCs (disease-​driving, on-​target drug effect) while sparing other key blood cell types (healthy, off-​target). For every patient, drugs could be prioritized with targeted pharmacoscopy drug response profiles, a strategy that, when applied to other blood cancers, has been proven to predict clinical response.
As every patient responds differently to different drug treatments, response profiles were integrated with large scale proteomics measurements (proteotyping) and clinical parameters. By this, we could stratify and gain molecular insight into drug responses. We could find that presence of the CALR mutation led to favorable response to BET inhibitors, particularly in the absence of upregulation of RAS pathway proteins. Furthermore, we found subgroups of patients molecularly characterized by proliferative and ER stress phenotypes. We could link these phenotypes to advanced disease and high CALR mutational burden, respectively, and importantly could prioritize specific drugs to target these groups of MF patients.

Overall, this study elucidates the drug response landscape of MF patients, and finds actionable molecular mechanisms that drive disease in subgroups of patients.