{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:52:33Z","timestamp":1787727153484,"version":"build-2784847793"},"reference-count":41,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>SMAD4<\/jats:italic>, a tumor suppressor gene, is lost in up to 60%\u201390% of pancreatic adenocarcinomas (PDAs). Loss of <jats:italic>SMAD4<\/jats:italic> allows tumor progression by upregulating autophagy, a cell survival mechanism that counteracts apoptosis and allows intracellular recycling of macromolecules. Hydroxychloroquine (HCQ) is an autophagy inhibitor. We studied whether HCQ treatment in <jats:italic>SMAD4<\/jats:italic> deficient PDA may prevent therapeutic resistance induced by autophagy upregulation. We retrospectively analyzed the SMAD4 status of patients with PDA enrolled in two prospective clinical trials evaluating pre\u2010operative HCQ. The first dose escalation trial demonstrated the safety of preoperative gemcitabine with HCQ (NCT01128296). More recently, a randomized trial of gemcitabine\/nab\u2010paclitaxel +\/\u2212 HCQ evaluated Evans Grade histopathologic response (NCT01978184). The effect of SMAD4 loss on response to HCQ and chemotherapy was studied for association with clinical outcome. Fisher\u2019s exact test and log\u2010rank test were used to assess response and survival. Fifty\u2010two patients receiving HCQ with neoadjuvant chemotherapy were studied. Twenty\u2010five patients had SMAD4 loss (48%). 76% of HCQ\u2010treated patients with SMAD4 loss obtained a histopathologic response greater than or equal to 2A, compared with only 37% with SMAD4 intact (<jats:italic>p\u00a0<\/jats:italic>=\u00a00.006). Although loss of SMAD4 has been associated with worse outcomes, in the current study, loss of SMAD4 was not associated with a detriment in median overall survival in HCQ\u2010treated patients (34.43\u00a0months in SMAD4 loss vs. 27.27\u00a0months in SMAD4 intact, <jats:italic>p\u00a0<\/jats:italic>=\u00a00.18). The addition of HCQ to neoadjuvant chemotherapy in patients with PDA may improve treatment response in those with SMAD4 loss. Further study of the relationship among SMAD4, autophagy, and treatment outcomes in PDA is warranted.<\/jats:p>","DOI":"10.1111\/cts.13029","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T11:45:48Z","timestamp":1621338348000},"page":"1822-1829","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["SMAD4 loss is associated with response to neoadjuvant chemotherapy plus hydroxychloroquine in patients with pancreatic adenocarcinoma"],"prefix":"10.1111","volume":"14","author":[{"given":"Naomi","family":"Fei","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology Department of Medicine West Virginia University Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijin","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics School of Public Health West Virginia University Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh","family":"Ramanathan","sequence":"additional","affiliation":[{"name":"Department of Surgery Banner MD Anderson Cancer Center Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa E.","family":"Hogg","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology Department of Surgery Northshore University Health System Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amer H.","family":"Zureikat","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology Department of Surgery University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Lotze","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology Department of Surgery University of Pittsburgh Pittsburgh Pennsylvania 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