Inverse Correlation of STAT3 and MEK Signaling Mediates Resistance to RAS Pathway Inhibition in Pancreatic Cancer

Cancer Research
Nagaraj S NagathihalliNipun B Merchant

Abstract

Major contributors to therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) include Kras mutations, a dense desmoplastic stroma that prevents drug delivery to the tumor, and activation of redundant signaling pathways. We have previously identified a mechanistic rationale for targeting STAT3 signaling to overcome therapeutic resistance in PDAC. In this study, we investigate the molecular mechanisms underlying the heterogeneous response to STAT3 and RAS pathway inhibition in PDAC. Effects of JAK/STAT3 inhibition (STAT3i) or MEK inhibition (MEKi) were established in Ptf1acre/+; LSL-KrasG12D/+ ; and Tgfbr2flox/flox (PKT) mice and patient-derived xenografts (PDX). Amphiregulin (AREG) levels were determined in serum from human patients with PDAC, LSL-KrasG12D/+;Trp53R172H/+;Pdx1Cre/+ (KPC), and PKT mice. MEKi/STAT3i-treated tumors were analyzed for integrity of the pancreas and the presence of cancer stem cells (CSC). We observed an inverse correlation between ERK and STAT3 phosphorylation. MEKi resulted in an immediate activation of STAT3, whereas STAT3i resulted in TACE-induced, AREG-dependent activation of EGFR and ERK. Combined MEKi/STAT3i sustained blockade of ERK, EGFR, and STAT3 signaling, overcoming resistance to ...Continue Reading

References

Jan 7, 2004·Cancer Cell·Sunil R HingoraniDavid A Tuveson
Jun 14, 2006·American Journal of Physiology. Cell Physiology·Haruhiko OhtsuSatoru Eguchi
Jan 16, 2007·The Journal of Clinical Investigation·Paraic A Kenny, Mina J Bissell
Aug 1, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Shirin Khambata-FordDavid J Mauro
Feb 19, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Nipun B MerchantRobert J Coffey
Sep 10, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Bart JacobsSabine Tejpar
Oct 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Martin L SosRoman K Thomas
Oct 15, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Benoît BusserAmandine Hurbin
Jan 27, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Nagathihalli S NagarajNipun B Merchant
Sep 15, 2012·Cancer Cell·Christine M ArditoJens T Siveke
Apr 30, 2013·Gastroenterology·Minoti V ApteStephen J Pandol
Apr 30, 2013·Gastroenterology·Marina Pasca di Magliano, Craig D Logsdon
Jul 31, 2013·Current Opinion in Gastroenterology·Meghna WaghrayDiane M Simeone
Apr 24, 2014·British Journal of Cancer·S EserD Saur
Jun 12, 2014·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Jeffrey R InfanteNgocdiep Le
Sep 30, 2014·The New England Journal of Medicine·Georgina V LongKeith Flaherty
Oct 25, 2014·Nature Reviews. Cancer·Hua YuRichard Jove
Oct 29, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Brinda AlagesanNabeel Bardeesy
Jan 7, 2015·CA: a Cancer Journal for Clinicians·Rebecca L SiegelAhmedin Jemal
Sep 25, 2015·Nature Reviews. Cancer·Christopher J CauntSimon J Cook
May 5, 2016·Physiological Reviews·Andreas WickiGongda Xue
Dec 31, 2016·Pancreatology : Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]·Patricia DauerSulagna Banerjee
Mar 1, 2016·Trends in Cancer·Qixia XuYu Sun

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Citations

Sep 6, 2019·Molecular Biology Reports·Arkadiusz GzilŁukasz Szylberg
Nov 7, 2019·Cancers·Kelsey L PolakMark W Jackson
Jun 24, 2020·The Journal of Clinical Investigation·Paarth B DodhiawalaKian-Huat Lim
Aug 17, 2020·Biomedicines·Friederike Inga Nollmann, Dietrich Alexander Ruess
Dec 7, 2020·Cell Death & Disease·Lakshana SreenivasanChinten James Lim
Jan 28, 2021·American Journal of Physiology. Gastrointestinal and Liver Physiology·Ce LiQiang Wang
Jan 30, 2021·Cancer Immunology Research·Reham AjinaLouis M Weiner
Feb 7, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Tenny MudiantoRavindra Uppaluri
May 5, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Kavita MallyaManeesh Jain
Sep 15, 2021·Molecular Cancer Therapeutics·Austin R DoschNipun B Merchant

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