Dual targeting of SLC6A14 and autophagy/macropinocytosis enhances therapeutic efficacy in pancreatic ductal adenocarcinoma

PDAC is highly desmoplastic and undergoes metabolic reprogramming to sustain their growth and proliferation. Our laboratory has identified SLC6A14, an amino acid transporter, as a novel drug target for PDAC. Genetic deletion of SLC6A14 or its pharmacological blockade with alpha-MLT attenuates PDAC growth by inducing amino acid deprivation. However, nutrient stress, particularly amino acid deprivation, can induce nutrient scavenging mechanisms like autophagy and macropinocytosis, thereby undermining the full anticancer potential of SLC6A14 blockade. To address this, the current work was conducted to test if SLC6A14 blockade induces autophagy and/or macropinocytosis and to further investigate if dual inhibition of SLC6A14 (alpha-MLT) and autophagy/macropinocytosis (HCQ) would yield a better therapeutic outcome in PDAC as opposed to targeting SLC6A14 alone. In vitro assays (MTT and colony formation) revealed that the combination treatment significantly reduced PDAC cell viability and clonogenic potential as opposed to monotherapy. Treatment model subcutaneous xenograft in athymic nude mice demonstrated a superior therapeutic outcome with the combination regimen. Collectively, our study demonstrates that the afore-described combination therapy creates a metabolic trap wherein alpha-MLT induces nutrient stress, while HCQ prevents autophagic and macropinocytosis compensation, thus culminating in a more potent tumor attenuation. This dual blockade represents a hitherto unexplored treatment strategy for PDAC.