Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival

Nutrient restriction reprograms cellular signaling and metabolic network to shape cancer phenotype. Lactate dehydrogenase A (LDHA) has a key role in aerobic glycolysis (the Warburg effect) through regeneration of the electron acceptor NAD + and is widely regarded as a desirable target for cancer therapeutics. However, the mechanisms of cellular response and adaptation to LDHA inhibition remain largely unknown. Here, we show that LDHA activity supports serine and aspartate biosynthesis. Surprisingly, however, LDHA inhibition fails to impact human melanoma cell proliferation, survival, or tumor growth. Reduced intracellular serine and aspartate following LDHA inhibition engage GCN2‐ATF4 signaling to initiate an expansive pro‐survival response. This includes the upregulation of glutamine transporter SLC1A5 and glutamine uptake, with concomitant build‐up of essential amino acids, and mTORC1 activation, to ameliorate the effects of LDHA inhibition. Tumors with low LDHA expression and melanoma patients acquiring resistance to MAPK signaling inhibitors, which target the Warburg effect, exhibit altered metabolic gene expression reminiscent of the ATF4‐mediated survival signaling. ATF4‐controlled survival mechanisms conferring synthetic vulnerability to the approaches targeting the Warburg effect offer efficacious therapeutic strategies. Synopsis Lactate Dehydrogenase A (LDHA) has a key role in tumor metabolism, but how malignant cells adapt to LDHA inhibition remains unclear. Here, LDHA blockade is shown to remodel amino acid biosynthesis by engaging ATF4‐dependent metabolic reprograming, suggesting new therapeutic strategies based on synthetic vulnerabilities. LDHA is dispensable for human melanoma cell proliferation and survival under normoxic conditions. LDHA inhibition suppresses serine and aspartate biosynthesis to activate GCN2‐ATF4‐mediated transcription. ATF4 induces SLC1A5 to increase uptake of glutamine and essential amino acid, thereby enhancing mTORC1 activity. Co‐targeting LDHA and mTORC1 shows a synergistic effect in suppressing melanoma cell proliferation and tumor growth. Graphical Abstract An ATF4‐dependent increase in the uptake of glutamine and essential amino acids allows melanoma cells to overcome pharmacological LDHA blockade by stimulating mTORC1 activity.