Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd..
Molecular-targeted therapies have demonstrated disappointing results against most advanced solid cancers. This may largey be attributed to irrational drug use against unselected cancers. We investigated the efficacy of dual MEK-PI3K drug therapy against KRAS mutated mucin 2 (MUC2)-secreting LS174T cells and patient-derived ex vivo and in vivo models of KRAS mutated mucinous colon/appendix cancers. These tumors demonstrate unique phenotypic and genotypic features that likely predict sensitivity to this targeted co-therapy. Co-treatment with MEK inhibitor (trametinib) and PI3K inhibitor (pictilisib)-induced synergistic cytotoxicity and intrinsic mitochondrial-mediated apoptosis in LS174T cells and tumor explants in vitro. Dual drug therapy also induced endoplasmic reticulum stress (ERS)-associated proteins (GRP78/BiP, ATF4, and CHOP). However, CHOP knock-down assays demonstrated that mitochondrial-mediated apoptosis in LS174T cells was not ERS-dependent. Dual drug therapy also significantly decreased MUC2 expression, MUC2 post-translational modification (palmitoylation) and secretion in LS174T cells, suggesting a simultaneous cytotoxic and mucin suppressive mechanism of action. We also demonstrated effective mucinous tumor growth suppression in ex vivo epithelial organoid (colonoid) cultures and in in vivo intraperitoneal patient-derived xenograft models derived from mucinous colon/appendix cancer. These promising preclinical data support a role for dual MEK-PI3K inhibitor therapy in mucinous colon/appendix cancers. We postulate that mucinous KRAS mutated cancers are especially vulnerable to this co-treatment based on their unique phenotypic and genotypic characteristics.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2020 |
---|---|
Erschienen: |
2020 |
Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
---|---|
Enthalten in: |
Cancer medicine - 9(2020), 5 vom: 21. März, Seite 1753-1767 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Dilly, Ashokkumar [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 23.04.2021 Date Revised 25.09.2022 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1002/cam4.2847 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM305569406 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM305569406 | ||
003 | DE-627 | ||
005 | 20231225121453.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231225s2020 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1002/cam4.2847 |2 doi | |
028 | 5 | 2 | |a pubmed24n1018.xml |
035 | |a (DE-627)NLM305569406 | ||
035 | |a (NLM)31958897 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Dilly, Ashokkumar |e verfasserin |4 aut | |
245 | 1 | 0 | |a Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors |
264 | 1 | |c 2020 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 23.04.2021 | ||
500 | |a Date Revised 25.09.2022 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. | ||
520 | |a Molecular-targeted therapies have demonstrated disappointing results against most advanced solid cancers. This may largey be attributed to irrational drug use against unselected cancers. We investigated the efficacy of dual MEK-PI3K drug therapy against KRAS mutated mucin 2 (MUC2)-secreting LS174T cells and patient-derived ex vivo and in vivo models of KRAS mutated mucinous colon/appendix cancers. These tumors demonstrate unique phenotypic and genotypic features that likely predict sensitivity to this targeted co-therapy. Co-treatment with MEK inhibitor (trametinib) and PI3K inhibitor (pictilisib)-induced synergistic cytotoxicity and intrinsic mitochondrial-mediated apoptosis in LS174T cells and tumor explants in vitro. Dual drug therapy also induced endoplasmic reticulum stress (ERS)-associated proteins (GRP78/BiP, ATF4, and CHOP). However, CHOP knock-down assays demonstrated that mitochondrial-mediated apoptosis in LS174T cells was not ERS-dependent. Dual drug therapy also significantly decreased MUC2 expression, MUC2 post-translational modification (palmitoylation) and secretion in LS174T cells, suggesting a simultaneous cytotoxic and mucin suppressive mechanism of action. We also demonstrated effective mucinous tumor growth suppression in ex vivo epithelial organoid (colonoid) cultures and in in vivo intraperitoneal patient-derived xenograft models derived from mucinous colon/appendix cancer. These promising preclinical data support a role for dual MEK-PI3K inhibitor therapy in mucinous colon/appendix cancers. We postulate that mucinous KRAS mutated cancers are especially vulnerable to this co-treatment based on their unique phenotypic and genotypic characteristics | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a MUC2; mucinous colon/appendix cancer; MEK | |
650 | 4 | |a PI3K | |
650 | 4 | |a colonoids | |
650 | 4 | |a xenograft | |
650 | 7 | |a 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine |2 NLM | |
650 | 7 | |a Endoplasmic Reticulum Chaperone BiP |2 NLM | |
650 | 7 | |a HSPA5 protein, human |2 NLM | |
650 | 7 | |a Hspa5 protein, mouse |2 NLM | |
650 | 7 | |a Indazoles |2 NLM | |
650 | 7 | |a KRAS protein, human |2 NLM | |
650 | 7 | |a MUC2 protein, human |2 NLM | |
650 | 7 | |a Mucin-2 |2 NLM | |
650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
650 | 7 | |a Pyridones |2 NLM | |
650 | 7 | |a Pyrimidinones |2 NLM | |
650 | 7 | |a Sulfonamides |2 NLM | |
650 | 7 | |a trametinib |2 NLM | |
650 | 7 | |a 33E86K87QN |2 NLM | |
650 | 7 | |a Mitogen-Activated Protein Kinase Kinases |2 NLM | |
650 | 7 | |a EC 2.7.12.2 |2 NLM | |
650 | 7 | |a Proto-Oncogene Proteins p21(ras) |2 NLM | |
650 | 7 | |a EC 3.6.5.2 |2 NLM | |
700 | 1 | |a Honick, Brendon D |e verfasserin |4 aut | |
700 | 1 | |a Lee, Yong J |e verfasserin |4 aut | |
700 | 1 | |a Bartlett, David L |e verfasserin |4 aut | |
700 | 1 | |a Choudry, Haroon A |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Cancer medicine |d 2012 |g 9(2020), 5 vom: 21. März, Seite 1753-1767 |w (DE-627)NLM224388460 |x 2045-7634 |7 nnns |
773 | 1 | 8 | |g volume:9 |g year:2020 |g number:5 |g day:21 |g month:03 |g pages:1753-1767 |
856 | 4 | 0 | |u http://dx.doi.org/10.1002/cam4.2847 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 9 |j 2020 |e 5 |b 21 |c 03 |h 1753-1767 |