Journal article
SMAD4 loss is associated with response to neoadjuvant chemotherapy plus hydroxychloroquine in patients with pancreatic adenocarcinoma
Clinical and translational science, Vol.14(5), pp.1822-1829
05/18/2021
DOI: 10.1111/cts.13029
PMCID: PMC8504806
PMID: 34002944
Abstract
SMAD4
, a tumor suppressor gene, is lost in up to 60%–90% of pancreatic adenocarcinomas (PDAs). Loss of
SMAD4
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
SMAD4
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‐operative HCQ. The first dose escalation trial demonstrated the safety of preoperative gemcitabine with HCQ (NCT01128296). More recently, a randomized trial of gemcitabine/nab‐paclitaxel +/− 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’s exact test and log‐rank test were used to assess response and survival. Fifty‐two patients receiving HCQ with neoadjuvant chemotherapy were studied. Twenty‐five patients had SMAD4 loss (48%). 76% of HCQ‐treated patients with SMAD4 loss obtained a histopathologic response greater than or equal to 2A, compared with only 37% with SMAD4 intact (
p
= 0.006). 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‐treated patients (34.43 months in SMAD4 loss vs. 27.27 months in SMAD4 intact,
p
= 0.18). 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.
Details
- Title: Subtitle
- SMAD4 loss is associated with response to neoadjuvant chemotherapy plus hydroxychloroquine in patients with pancreatic adenocarcinoma
- Creators
- Naomi Fei - West Virginia UniversitySijin Wen - West Virginia UniversityRajesh Ramanathan - The University of Texas MD Anderson Cancer CenterMelissa E. Hogg - NorthShore University HealthSystemAmer H. Zureikat - University of PittsburghMichael T. Lotze - University of PittsburghNathan Bahary - University of PittsburghAatur D. Singhi - University of PittsburghHerbert J. Zeh - The University of Texas Southwestern Medical CenterBrian A. Boone - West Virginia University
- Resource Type
- Journal article
- Publication Details
- Clinical and translational science, Vol.14(5), pp.1822-1829
- DOI
- 10.1111/cts.13029
- PMID
- 34002944
- PMCID
- PMC8504806
- NLM abbreviation
- Clin Transl Sci
- ISSN
- 1752-8054
- eISSN
- 1752-8062
- Publisher
- John Wiley and Sons Inc
- Alternative title
- SMAD4 loss and HCQ Response in PDA
- Language
- English
- Date published
- 05/18/2021
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359865202771
Metrics
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