DLL4 and pachyonychia congenita: Previous research has shown that excessive activation of the DLL4/Notch pathway in PDAC causes defective angiogenesis within tumors, resulting in low efficiency of chemotherapeutic drug delivery in vivo and enhanced multi-drug chemoresistance.471 Another study revealed that GEM, a first-line chemotherapy agent for PDAC, induces Midkine expression in a dose-dependent manner.472 Furthermore, Midkine interacts with Notch2 to activate Notch signaling, driving PDAC resistance to GEM.472 Similar to PDAC, chemotherapy resistance is a major challenge for PC.