EGFR and Prion protein promote signaling via FOXO3a‐KLF5 resulting in clinical resistance to platinum agents in colorectal cancer

Abstract

Epidermal growth factor receptor ( EGFR ) supports colorectal cancer progression via oncogenic signaling. Anti‐ EGFR therapy is being investigated as a clinical option for colorectal cancer, and an observed interaction between EGFR and Prion protein has been detected in neuronal cells. We hypothesized that Pr P C expression levels may regulate EGFR signaling and that detailed understanding of this signaling pathway may enable identification of resistance mechanisms and new actionable targets in colorectal cancer. We performed molecular pathway analysis following knockdown of Pr P C or inhibition of EGFR signaling via gefitinib to identify changes in expression of key signaling proteins that determine cellular sensitivity or resistance to cisplatin. Expression of these proteins was examined in matched primary and metastatic patient samples and was correlated for resistance to therapy and progression of disease. Utilizing three colorectal cancer cell lines, we observed a correlation between high expression of Pr P C and resistance to cisplatin. Investigation of molecular signaling in a resistant cell line revealed that Pr P C contributed to signaling via colocalization with EGFR , which could be overcome by targeting p38 mitogen‐activated protein kinases (p38 MAPK ). We revealed that the level of Krüppel‐like factor 5 ( KLF 5), a target downstream of p38 MAPK , was predictive for cell line and patient response to platinum agents. Further, high KLF 5 expression was observed in BRAF ‐mutant colorectal cancer. Our study indicates that the EGFR to KLF 5 pathway is predictive of patient progression on platinum‐based therapy.

Gel-Free 3D Tumoroids with Stem Cell Properties Modeling Drug Resistance to Cisplatin and Imatinib in Metastatic Colorectal Cancer

“…Pou5f1), and cMyc. Moreover, Atkinson et al reported that EGFR and Prion protein promoted signaling via FOXO3a-KLF5 resulting in clinical resistance to platinum agents in CRC [41]. These data indicate that the drug resistance and recurrence in cancer may involve increased CSC properties.…”

Knockdown of KLF5 promotes cisplatin‐induced cell apoptosis via regulating DNA damage checkpoint proteins in non‐small cell lung cancer

“…Multiple studies have shown that KLF5 plays a role in cisplatin resistance in various tumors. In colorectal cancer, KLF5 is predictive for cell line and patient response to platinum agents . In ovarian cancer cell lines, silencing KLF5 by small interfering RNA sensitizes cells to apoptosis induced by cisplatin .…”

“…In colorectal cancer, KLF5 is predictive for cell line and patient response to platinum agents. 20 In ovarian cancer cell lines, silencing KLF5 by small interfering RNA sensitizes cells to apoptosis induced by cisplatin. 21 A previous study reported that KLF5 knockdown could suppress hypoxia-induced cisplatin resistance in NSCLC, probably via inactivation of the PI3K/Akt/ mTOR pathway; 13 however, the study failed to mention the prognostic value of KLF5 and its underlying roles in the DDR in NSCLC.…”

The Role of Cellular Prion Protein in Promoting Stemness and Differentiation in Cancer

“…Disruption of PrP C /P-gp complex has profound effects on tumor survival and aggressiveness, since it markedly reduces the anti-apoptotic activity, while promoting the reversal of PrP C -mediated drug resistance in MDR breast cancer cells [ 135 ]. Furthermore, the direct interaction between PrP C and EGFR is determinant for cisplatin/oxaliplatin resistance in colorectal cancer cells via FOXO3a-Krüppel-like factor 5 (KLF5) signaling, thus contributing to the development of metastases and poor outcome in CRC patients [ 155 ]. Again, PrP C /CD44 interaction promotes chemoresistance and tumor progression in MDR breast cancer cells [ 132 ].…”