Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer

Schmidt, Éva; Lamprecht, Sebastian; Blaj, Cristina; Schaaf, Christian; Krebs, Stefan; Blum, Helmut; Hermeking, Heiko; Jung, Andreas; Kirchner, Thomas; Horst, David

doi:10.1084/jem.20171455

Cited by 34 publications

(34 citation statements)

References 38 publications

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“…We previously showed that combined inhibition of MAPK and NOTCH signaling slowed tumor growth in colon cancer xenografts . In order to compare these therapeutic effects with chemotherapy, we treated SW480 and SW1222 xenografts for longer terms of up to 31 days with 5‐FU chemotherapy or, for MAPK and NOTCH inhibition, with AZD and DBZ (Figure A).…”

Section: Resultsmentioning

confidence: 99%

“…SW480 carries mutated p53(R273H/P309S), truncated APC(Q1338*), and also has an activating mutation in KRAS(G12V). Both cell lines were derived from colorectal adenocarcinomas, are microsatellite stable and tumorigenic in NOD/SCID mice . Cell line identity was verified by short‐tandem repeat profiling, and both cell lines tested negative for Mycoplasma contamination.…”

Section: Methodsmentioning

confidence: 99%

“…Besides WNT and MAPK signaling, activation of NOTCH signaling has been observed in colorectal cancer. Although in treatment trials, NOTCH repression by γ‐secretase inhibitors has so far been disappointing, we recently showed that dual inhibition of MAPK and NOTCH signaling by MEK and γ‐secretase inhibitors strongly repressed colon cancer growth . However, it remains to be determined whether combined MAPK and NOTCH repression may add benefit to established chemotherapeutic regimens.…”

Section: Introductionmentioning

confidence: 99%

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In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer

et al. 2019

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Patients with advanced colorectal cancer often are treated with systemic cytotoxic therapy using fluorouracil (5‐FU), oxaliplatin, irinotecan, and FOLFOX or FOLFIRI combination protocols. Additionally, signaling pathways that are active in colorectal cancer can be therapeutically targeted. Herein, we examined whether chemotherapy impacts on WNT, MAPK and NOTCH signaling pathways in xenograft models of colon cancer. Furthermore, we tested whether combining chemotherapy with MAPK and NOTCH inhibition has superior therapeutic effects. We show that colon cancer cells with high WNT, MAPK and NOTCH activity are variably affected but generally persist in xenograft tumors under different chemotherapeutic regimens, indicating limited effects of cytotoxic therapy on oncogenic signaling pathways. Although these results provided a rationale to additionally target pathway activity, we found no significant increase in therapy response when combining MAPK and NOTCH inhibition with fluorouracil chemotherapy. We attribute this finding to a decrease in tumor cell proliferation upon MAPK and NOTCH inhibition, resulting in reduced effectiveness of cytotoxic treatment. Therapeutic benefits of combining chemotherapy with targeting of oncogenic signaling pathways must therefore be critically evaluated for patients with colorectal cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer

et al. 2019

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“…Interactions between MAPK with TGF‐β, COX‐2, and NOTCH is also important to be considered (Schmidt et al, ). MAPK exhibits a bidirectional cross‐talking with TGF‐β and COX‐2.…”

Section: Mapk Cross‐talking With Other Signaling Pathwaysmentioning

confidence: 99%

“…NOTCH is another tumorigenic signaling frequently activated in most cancers, and its interaction with MAPK is related to cancer plasticity and metastasis. The activity of both signaling is concentrated to the infiltrative margin of cancer where cancer stem cells (CSCs) reside and cancer cells undergo EMT (Schmidt et al, ) (Figure B).…”

Section: Mapk Cross‐talking With Other Signaling Pathwaysmentioning

confidence: 99%

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

Najafi

Ahmadi

Mortezaee

2019

Cell Biology International

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Mitogen-activated protein kinase (MAPK) signaling pathway is activated in a wide spectrum of human tumors, exhibiting cardinal oncogenic roles and sustained inhibition of this pathway is considered as a primary goal in clinic. Within this pathway, receptor tyrosine kinases such as epithelial growth factor receptor, mesenchymal-epithelial transition, and AXL act as upstream regulators of RAS/RAF/MEK/extracellular-signal-regulated kinase. MAPK signaling is active in both early and advanced stages of tumorigenesis, and it promotes tumor proliferation, survival, and metastasis. MAPK regulatory effects on cellular constituent of the tumor microenvironment is for immunosuppressive purposes. Cross-talking between MAPK with oncogenic signaling pathways including WNT, cyclooxygenase-2, transforming growth factor-β, NOTCH and (in particular) with phosphatidylinositol 3-kinase is contributed to the multiplication of tumor progression and drug resistance. Developing resistance (intrinsic or acquired) to MAPK-targeted therapy also occurs due to heterogeneity of tumors along with mutations and negative feedback loop of interactions exist between various kinases causing rebound activation of this signaling. Multidrug regimen is a preferred therapeutic avenue for targeting MAPK signaling. To enhance patient tolerance and to mitigate potential adversarial effects related to the combination therapy, determination of a desired dose and drug along with pre-evaluation of cancer-type-specific kinase mutation and sensitivity, especially for patients receiving triplet therapy is an urgent need.

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