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]
Honick, Brendon D [VerfasserIn]
Lee, Yong J [VerfasserIn]
Bartlett, David L [VerfasserIn]
Choudry, Haroon A [VerfasserIn]

Links:

Volltext

Themen:

2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
33E86K87QN
Colonoids
EC 2.7.12.2
EC 3.6.5.2
Endoplasmic Reticulum Chaperone BiP
HSPA5 protein, human
Hspa5 protein, mouse
Indazoles
Journal Article
KRAS protein, human
MUC2; mucinous colon/appendix cancer; MEK
MUC2 protein, human
Mitogen-Activated Protein Kinase Kinases
Mucin-2
PI3K
Protein Kinase Inhibitors
Proto-Oncogene Proteins p21(ras)
Pyridones
Pyrimidinones
Research Support, N.I.H., Extramural
Sulfonamides
Trametinib
Xenograft

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