RSPO2 and cancer: The mechanism suggests that porcupine inhibition will be mainly effective in cancers that are Wnt dependent but do not harbor downstream Wnt activating mutations in genes such as APC or CTNNB1. Instead, cancers that rely on upstream Wnt activating events, including the recently reported fusion events involving RSPO2 and RSPO3 in a small percentage of APC wild type CRCs [5,101] or RNF43 mutant pancreatic cancers [102].