acquired resistance to hedgehog pathway inhibitors has been reported in the clinical setting and upregulation of noncanonical hedgehog signaling is one of the major underlying mechanisms behind this resistance . 
 as demonstrated in our recent study , greater clinical efficacy might be achieved by focusing on downstream targets of the chemokine - activated noncanonical hedgehog signaling pathway such as bcar4 and phospho - gli2 ( ser149 ) .