While targeting the PI3K/AKT pathway is sufficient to kill disseminating CR-CSCs, we found that HER2 is constitutively expressed in CR-CSCs and that the simultaneous targeting of HER2, PI3K and MEK neutralises the protective effect of tumour stroma and induces tumour regression, even in the presence of aggressive mutational backgrounds. This evidence concerns the gene MAP2K7 and neoplasm.