Targeting a MYC-directed metabolic vulnerability sensitizes tyrosine kinase inhibitor therapy with selectivity

Abstract A key strategy for precision therapy lies in identifying and targeting tumor cell-specific metabolic vulnerabilities to develop effective combination treatments. In this study, we demonstrate that vandetanib, a multi-kinase inhibitor, acts as a potent transcriptional repressor of the serine synthesis pathway (SSP) in non-small cell lung cancer (NSCLCs). Mechanistically, vandetanib acts by suppressing the oncogenic transcription factor MYC, which exerts a greater regulatory weight on SSP transcription than the canonical GCN2–ATF4 adaptive amino acid response (AAR) axis. This MYC-directed SSP blockade impairs tumor adaptation to serine/glycine (SG) deprivation, inducing cooperative cytotoxicity both in vitro and in vivo. Crucially, normal cells rely on the GCN2–ATF4 pathway rather than MYC for SSP regulation, thereby sparing them from toxicity. The combination of vandetanib with SG restriction achieves potent tumor suppression with an improved safety profile. Our work establishes a “metabolic sensitization” paradigm wherein targeting oncogene-specific transcriptional nodes disrupts tumor metabolic adaptability, offering a highly selective strategy to overcome TKI resistance.