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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 \u03b1-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 whether SLC6A14 blockade induces autophagy and\/or macropinocytosis and to further investigate whether dual inhibition of SLC6A14 (\u03b1-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. The 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 \u03b1-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.<\/jats:p>","DOI":"10.1042\/bcj20250155","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T08:20:22Z","timestamp":1775722822000},"page":"1369-1390","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dual targeting of SLC6A14 and autophagy\/macropinocytosis enhances therapeutic efficacy in pancreatic ductal adenocarcinoma"],"prefix":"10.1042","volume":"483","author":[{"given":"Mosharaf","family":"Mahmud Syed","sequence":"first","affiliation":[{"name":"1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devaraja","family":"Rajasekaran","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souad\u00a0R.","family":"Sennoune","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanima","family":"Sharker","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Sanchez","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary\u00a0Katherine","family":"Jurek","sequence":"additional","affiliation":[{"name":"2Department of Psychiatry, Tufts Medical Center, 800 Washington St., Boston, MA 02111, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longfa","family":"Kou","sequence":"additional","affiliation":[{"name":"3Department of Pharmacy, Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijie","family":"Chen","sequence":"additional","affiliation":[{"name":"3Department of Pharmacy, Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadivel","family":"Ganapathy","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6927-075X","authenticated-orcid":false,"given":"Yangzom\u00a0D.","family":"Bhutia","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"2026070205414310100_B1","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/j.molmed.2023.03.002","article-title":"Fibroblasts in pancreatic cancer: molecular and clinical perspectives","volume":"29","author":"Rebelo","year":"2023","journal-title":"Trends Mol. 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