In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer

TY - JOUR

T1 - In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer

AU - Spartalis, Christoph

AU - Schmidt, Eva Marina

AU - Elmasry, Manal

AU - Schulz, Gerald Bastian

AU - Kirchner, Thomas

AU - Horst, David

N1 - © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

PY - 2019/8

Y1 - 2019/8

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Combined Chemotherapy Protocols/pharmacology

KW - Carcinogenesis/drug effects

KW - Cell Proliferation/drug effects

KW - Colorectal Neoplasms/drug therapy

KW - Female

KW - Fluorouracil/pharmacology

KW - Heterografts/drug effects

KW - Humans

KW - Leucovorin/pharmacology

KW - Male

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Oncogenes/drug effects

KW - Organoplatinum Compounds/pharmacology

KW - Signal Transduction/drug effects

U2 - 10.1111/cas.14077

DO - 10.1111/cas.14077

M3 - SCORING: Journal article

C2 - 31119819

VL - 110

SP - 2529

EP - 2539

JO - CANCER SCI

JF - CANCER SCI

SN - 1347-9032

IS - 8

ER -