To experimentally test our hypothesis that the dependence of CSCs, rather than bulk tumor cells, to the targeted pathway determines the molecular mechanism of therapeutic resistance (Fig. 1A), we first used an autochthonous SHH medulloblastoma mouse model (FSmoM2;hGFAP-cre) in which the activated SMO (SMO-M2) allele is conditionally expressed upon Cre recombinase expression (34). Here, SMO is linked to medulloblastoma.