In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer
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In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer. / Spartalis, Christoph; Schmidt, Eva Marina; Elmasry, Manal; Schulz, Gerald Bastian; Kirchner, Thomas; Horst, David.
In: CANCER SCI, Vol. 110, No. 8, 08.2019, p. 2529-2539.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -