Considering genetic alterations beyond BTKC481S mutation as the primary cause, Rahal et al. demonstrated loss of function mutation in NF-κB inhibitors (TRAF2, TRAF3, and BIRC3) in ibrutinib-resistant MCL cell lines (n = 6) causing dependency of resistant cells on the MAP3K14 pathway which in turn activated the alternative NF-κB survival signaling. Here, BIRC3 is linked to mantle cell lymphoma.