The adaptive nature of cancer is a major obstacle limiting durable treatment responses. Histological transformation (HT) is a process whereby one cancer changes into a categorically different tumor type, often following treatment with targeted therapy. Best characterized in lung and prostate adenocarcinomas, HT is particularly disconcerting because the resultant cancer no longer depends on the initial oncogenic driver program, is therapeutically recalcitrant, and is often highly metastatic. Partly because HT is technically difficult to study, this process remains poorly described. As newer therapies broaden the scope of oncogenic drivers that can be targeted, HT may become more prevalent, highlighting the need for further research to dissect these phenomena. We propose that modern experimental and analytical tools present an opportunity to advance our understanding and improve our clinical management of histologically transforming cancers.
