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The epithelial-specific cell adhesion molecule (EpCAM) modulates cell adhesion and proliferation. Its overexpression correlates with tumor cell proliferation, and EpCAM is a therapeutic target. In the February issue of Nature Cell Biology, Maetzel et al. demonstrate that proliferative responses to EpCAM require regulated intramembrane proteolysis and a nucleocytoplasmic intracellular domain fragment. [Copyright &y& Elsevier]

We developed neratinib-resistant HER2 -mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Primary and acquired neratinib resistance in HER2 -mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1 hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivity to the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimus and neratinib potently arrested the growth of neratinib-resistant xenografts and organoids established from neratinib-resistant PDXs. RNA and whole-exome sequencing revealed RAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencing of HER2- mutant tumors clinically refractory to neratinib, as well as circulating tumor DNA profiling of patients who progressed on neratinib, showed enrichment of genomic alterations that converge to activate the mTOR pathway. • Neratinib resistance in HER2 -mutant cancers is associated with TORC1 hyperactivation • Multiple mechanisms converge on TORC1 signaling to promote neratinib resistance • Combination with TORC1 inhibitor everolimus restores sensitivity to neratinib In brief, Sudhan et al. identify that hyperactivation of TORC1 restores HER2 downstream signaling to drive neratinib resistance across histologically distinct HER2 -mutant cancers. The combination of TORC1 inhibitor everolimus and neratinib arrests the growth of neratinib-resistant cells, organoids, and xenografts. [ABSTRACT FROM AUTHOR]