Exploiting Acquired Drug Resistance in Pancreatic Cancer through Selective Covalent Targeting of MAP2K4/7

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and remains largely refractory to targeted therapy despite its near-universal dependence on oncogenic KRAS. Single-agent KRAS inhibitors often fail due to adaptive resistance mechanisms that emerge under pharmacologic pressure. Previous studies combining MAP2K4 inhibition with KRASG12C-targeted therapy determined that partial JNK suppression can enhance anticancer responses. Here, we extend this concept to PDAC, which is predominantly driven by KRASG12D mutations, and demonstrate that full JNK pathway inactivation restores sensitivity to KRAS inhibition in resistant cells. Using selective MAP2K4, MAP2K7, or combined inhibitors, we show that more extensive JNK suppression disables the feedback loop that reactivates KRAS signaling. In contrast, KRASG12D inhibitor-sensitive cells derive no benefit from JNK pathway inhibition, revealing a resistance-specific vulnerability amenable to therapeutic exploitation.