LAUSR

Small-cell neuroendocrine (SCN) cancers are an aggressive cancer subtype. Transdifferentiation toward an SCN phenotype has been reported as a resistance route in response to targeted therapies. This has important consequences in that SCN cancers, once considered rare in many tissue types, may become increasingly common with the emergence of resistance cases. Here, we identified a molecular convergence to an SCN state that is more widespread across various epithelial cancers than previously realized, with these additional cases associated with poor prognosis. More broadly, non-SCN metastases have higher expression of SCN-associated transcription factors than non-SCN primary tumors. Drug sensitivity and gene dependency screens demonstrate that these convergent SCN cancers have shared vulnerabilities. These common vulnerabilities are found across unannotated SCN-like epithelial cases, pediatric small round blue cell tumors, and unexpectedly in hematologic malignancies. The SCN convergent phenotype and common sensitivity profiles with hematologic cancers can guide treatment options beyond the limitations of tissue-specific targeted therapies.