Our findings also uncover vulnerabilities of CREBBP-deficient cancers: even though oncogenic signaling does not induce a general destabilization of the ERN in this context, we observed a “local” synthetic fragility of the HAT subnetwork, which suggests that combinatorial targeting of multiple HATs may have deleterious effects on cancer cells while sparing their normal counterparts. The gene discussed is CREBBP; the disease is cancer.