Dr Nabeel Bardeesy presented new insights into therapeutic resistance in cholangiocarcinoma (CCA), underscoring a central challenge in the field: current targeted therapies offer meaningful but incomplete benefit, with resistance emerging in most patients. Supported by initiatives such as the Cholangiocarcinoma Foundation’s Cure Cholangiocarcinoma Think Tank (C2T2), his work focuses on understanding and overcoming these underlying mechanisms to enable more durable treatment strategies.
Despite advances in identifying actionable mutations such as FGFR and IDH, treatment outcomes remain limited. FGFR inhibitors, for example, induce tumor shrinkage in approximately 40% of patients, but responses are rarely durable. Resistance frequently arises through multiple mechanisms, including secondary mutations in FGFR, activation of bypass pathways such as EGFR signaling, and intratumoral heterogeneity, where distinct resistant clones emerge simultaneously.
To better understand tumor behavior, Dr. Bardeesy’s team has leveraged large-scale functional genomics and developed mouse models which closely recapitulate the molecular and histologic features of FGFR-driven CCA, providing a robust platform to study tumor evolution and test new treatment strategies. These systems have been instrumental in uncovering how tumors evolve under therapeutic pressure.
Using these models, the team identified adaptive EGFR signaling as a key driver of resistance to FGFR inhibition. This finding led to the evaluation of combined FGFR and EGFR blockade, which demonstrated strong synergy and tumor regression in preclinical studies. To further address the diversity of such mechanisms, broader approaches such as pan-RAS inhibitors are also being explored, showing activity across multiple resistance pathways and achieving meaningful tumor suppression in FGFR-resistant models. These strategies are now moving toward clinical evaluation.
Beyond tumor-intrinsic resistance, the work also emphasizes the role of the tumor microenvironment in shaping treatment response. CCA tumors exist within complex ecosystems, where immune cells influence disease progression and therapeutic outcomes. In preclinical models, FGFR-driven tumors exhibited dynamic immune changes, including activation of interferon-related programs and increased infiltration of CD8-positive T cells. Although early attempts to use FGFR inhibitors with immunotherapy, such as PD-L1 blockade, have shown limited efficacy, these findings suggest that more refined strategies may unlock the potential of combination approaches.
Together, these studies frame resistance not as a single mechanism but as a multifaceted process involving both tumor cell adaptation and microenvironmental factors. Addressing this complexity will require integrated strategies that target multiple pathways concurrently while accounting for immune context.
Dr. Bardeesy concluded by emphasizing that continued progress will depend on integrating biological insight with collaborative research efforts. Programs like C2T2 have been critical in enabling these advances, supporting the development of shared resources and accelerating the translation of discovery into therapeutic innovation.
Source: Bardeesy N. Therapy resistance and combination strategies in cholangiocarcinoma: navigating adaptive responses and lineage states. Presented at: 2026 Annual Cholangiocarcinoma Foundation Conference. May 1-3, 2026; Salt Lake City, UT.
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