vCATCH Maps Cellular Targets of Cancer Drugs throughout the Entire Body

A key step of preclinical drug development is understanding how potential therapies may engage targets across tissues within a patient, and the comprehensive quantification of these binding profiles in mammalian models, such as the adult mouse, is essential for predicting therapeutic activity and toxicity in human patients. To this end, Pang, Leung, and colleagues developed vCATCH, a volumetric tissue clearing and click chemistry platform that enables the uniform labeling of covalent drug analogs throughout the entire mouse body at cellular resolution. Challenges that initially limited efficient whole-body analysis via standard click chemistry were addressed by the introduction of pre-reaction copper saturation and repeated click reactions, to overcome endogenous copper binding and to improve tissue penetration. After optimization of the technique to quantify cell targets of a monoamine oxidase inhibitor analog within the whole mouse brain, vCATCH was used to profile two clinically approved covalent tyrosine kinase inhibitors, afatinib and ibrutinib. vCATCH analysis of alkyne analogs of the two inhibitors demonstrated organ-level distributions throughout the mouse that were consistent with established autoradiography data from the FDA. Moreover, vCATCH provided high-resolution intra-organ distribution detail, as the analysis revealed that both analogs of ibrutinib and afatinib strongly bound to circular structures within the bone and the spleen, suggestive of vasculature-associated binding. Within the same organ, the two drugs displayed different intra-organ patterns within the lung, liver, and kidneys, for example. Beyond spatial organ-level measurements, vCATCH also shed light on cell-level distributions, confirming that afatinib and ibrutinib primarily interacted with the expected EGFR+ and BTK+ target cells, respectively, and further revealing binding of afatinib to hepatocytes, as well as to a lesser degree macrophages and T cells, while ibrutinib demonstrated binding to higher proportion of macrophages, as well as notably large proportion of T cells, despite their low BTK expression. Taken together, these findings provide evidence that vCATCH enables body-wide quantitative mapping of covalent drug targets within mice with spatial and cellular precision that bridges pharmacokinetics with tissue specific drug engagement relevant to clinical safety and efficacy.Pang Z, Leung VH, Wang CC, Attarpour A, Rinaldi A, Shen H, et al. Mapping cellular targets of covalent cancer drugs in the entire mammalian body. Cell 2025 Dec 22 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.