Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors

Ashokkumar Dilly, Brendon D. Honick, Yong J. Lee, David L. Bartlett, Haroon A. Choudry

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1753-1767
Number of pages15
JournalCancer Medicine
Volume9
Issue number5
DOIs
StatePublished - 1 Mar 2020
Externally publishedYes

Keywords

  • MUC2; mucinous colon/appendix cancer; MEK
  • PI3K
  • colonoids
  • xenograft

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