Targeted Protein Degraders (PROTACs) Overcome KRAS Inhibitor Resistance and Remodel Antitumor Immunity in Lung Cancer

For nearly forty years, KRAS sat on oncology's list of targets everyone wanted and no one could reach — a smooth, pocket-less GTPase whose picomolar affinity for GTP made conventional occupancy-driven chemistry a poor fit. Discovery of a cryptic switch-II pocket changed that calculus, delivering covalent G12C inhibitors such as sotorasib and adagrasib, yet clinical benefit has proven frustratingly transient: secondary pocket mutations, KRAS amplification, and adaptive feedback through wild-type RAS and upstream receptor tyrosine kinases routinely restore signaling within months. This review asks why that keeps happening and traces a different strategy built to answer it directly — targeted protein degradation, particularly proteolysis-targeting chimeras (PROTACs), which hijack the ubiquitin–proteasome system to eliminate the target physically rather than merely block it. We synthesize the mechanistic logic separating heterobifunctional PROTACs from monovalent molecular glues and non-proteasomal chimeras (LYTACs, AUTACs, ATTECs), then trace the KRAS-specific degrader lineage from the failed reporter-only compound XY-4-88 through the first endogenous degrader LC-2, to clinically advanced agents such as ASP3082 and compact FBXO28-recruiting degraders including DJX-A-KM. Because degradation depends on ternary-complex cooperativity rather than sustained occupancy, these molecules retain activity against resistant alleles and remodel the tumor immune microenvironment in ways that synergize with checkpoint blockade. We close by weighing unresolved translational obstacles — beyond-rule-of-five physicochemistry, emerging E3 ligase-specific resistance, and the delivery and computational innovations now being deployed against them. Taken together, the evidence positions degrader chemistry as a distinct, resistance-resilient complement to KRAS inhibition in lung adenocarcinoma, though clinical confirmation remains, for now, incomplete.