Cholangiocarcinoma (CCA) is a heterogeneous disease of the biliary tract with a diverse molecular landscape; however, effective targeted therapy options are limited, and high rates of primary and acquired resistance occur, underscoring the need for alternative therapeutic targets to improve patient outcomes.1
At the 2024 Cholangiocarcinoma Foundation Annual Conference, Jennifer Tomlinson, MD, discussed the Yes-associated protein (YAP) and transcriptional enhancer associate domain (TEAD) signaling pathway as a potential novel target for therapeutic intervention in CCA.
YAP is a transcriptional co-activator that interacts with TEAD to control the expression of target genes, thereby regulating cell proliferation and survival. YAP is a critical oncogene overexpressed in CCA, and its nuclear-activated form has been shown to drive tumorigenesis and evade apoptosis.
Dr Tomlinson noted that since YAP has been difficult to target pharmacologically, ongoing efforts are investigating other therapeutic targets in the YAP pathway, including TEAD and the upstream YAP activator, lymphocyte-specific protein tyrosine kinase (LCK).
Preclinical evidence indicates that inhibition of LCK with a small-molecule tyrosine kinase inhibitor causes downregulation of YAP activity. Using CCA models, LCK inhibition was shown to decrease YAP activity. Nanovesicle-mediated inhibition of YAP, WW domain–containing transcription regulator, and LCK in CCA tumor–bearing mice demonstrated a significant reduction in tumor burden.
Given that TEADs are key mediators of the carcinogenic activity of YAP, TEAD was evaluated as a viable therapeutic target in CCA. The small molecule inhibitor CTX 1009685 is a TEAD 1/3/4 inhibitor tested in syngeneic mouse and patient-derived xenograft (PDX) CCA models.
In the syngeneic CCA models implanted with murine CCA cell lines, CTX 1009685–treated tumors in the CTX group were significantly smaller compared with the vehicle-treated group and showed decreased expression of YAP target genes.
However, in immunodeficient PDX models of CCA, CTX 1009685 was not more effective than the vehicle in controlling tumor growth. Profiling the tumor immune microenvironment of CCA tumors from syngeneic mice treated with CTX 1009685 did not detect any signals.
In terms of future directions, several additional studies are proposed to dissect YAP from TEAD signaling and identify novel targeting approaches. These include investigating pan-TEAD inhibitors, using nanovesicles to deliver pan-TEAD small interfering ribonucleic acid, assessing combination strategies with cytotoxic chemotherapy, and utilizing genetic inducible knockout models of YAP compared with TEAD in animal studies.2
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