Lineage plasticity sensitizes FGFR3-mutant bladder cancer to FGFR inhibitors

Lineage plasticity – the ability of cells to switch between differentiation states – is an enigmatic process that has been increasingly associated with drug resistance in cancer. Upending this paradigm, we demonstrate that lineage plasticity can also be harnessed to sensitize cancer to a targeted therapy. We have discovered that enforcing a luminal to basal lineage switch through inhibiting either luminal lineage-specifying transcription factors (lsTFs) or CDK8 leads to synergy with FGFR inhibitors in FGFR3-mutant bladder cancer. Indeed, FGFR plus CDK8 inhibition induces sustained tumor regressions with no obvious toxicity in mouse models. Our central hypothesis is that gaining a deeper mechanistic understanding of lineage plasticity and its cellular effects will enable its improved therapeutic utilization. We have designed a systematic dissection of 1) the processes by which CDK8 and lsTFs regulate lineage plasticity, employing genome-wide epigenetic and gene-specific functional assays; 2) the role of lineage state in clinical FGFRi efficacy, using cutting-edge single cell-resolution spatial transcriptomics to interrogate a unique cohort of patient samples and building a prospective organoid bank as patient avatars; and 3) the translational value of FGFR plus CDK8 inhibition, by conducting additional preclinical trials including in immunocompetent mice with or without additional PD1 blockade. The use of mice is a necessary step towards establishing a future clinical trial, as extensive positive data will help attract industry support for testing the combination therapies which we strongly believe will one day benefit thousands of patients. Together, these aims respond to the Biology of Bladder Cancer FOA and forge a biological and translational path towards the exploitation of lineage plasticity as a paradigm shift in cancer therapy. Project Number: 1R01CA311111-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Lawrence Kwong (+2 co-PIs) | Institution: UNIVERSITY OF TX MD ANDERSON CAN CTR, HOUSTON, TX | Award Amount: $637,473 | Activity Code: R01 | Study Section: Mechanisms of Cancer Therapeutics C Study Section [MCTC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11337716