Involvement of clusterin expression in the refractory response of pancreatic cancer cells to a MEK inhibitor

Abstract

Constitutive activation of the mitogen‐activated protein kinase (MAPK) signaling pathway is essential for tumorigenesis of pancreatic ductal adenocarcinoma (PDAC). To date, however, almost all clinical trials of inhibitor targeting this pathway have failed to improve the outcome of patients with PDAC. We found that implanted MIA Paca2, a human PDAC cell line sensitive to a MAPK inhibitor, PD0325901, became refractory within a week after treatment. By comparing the expression profiles of MIA Paca2 before and after acquisition of the refractoriness to PD0325901, we identified clusterin (CLU) as a candidate gene involved. CLU was shown to be induced immediately after treatment with PD0325901 or expressed primarily in more than half of PDAC cell lines, enhancing cell viability by escaping from apoptosis. A combination of PD0325901 and CLU downregulation was found to synergistically or additively reduce the proliferation of PDAC cells. In surgically resected PDAC tissues, overexpression of CLU in cancer cells was observed immunohistochemically in approximately half of the cases studied. Collectively, our findings highlight the mechanisms responsible for the rapid refractory response to MEK inhibitor in PDAC cells, suggesting a novel therapeutic strategy that could be applicable to patients with PDAC using inhibitor targeting the MAPK signaling pathway and CLU.

The Role of Apolipoproteins in the Commonest Cancers: A Review

“…Additionally, CLU is linked to an early resistance to MEK inhibitors, a type of cancer treatment targeting the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, CLU could play a crucial role in the development of a novel therapeutic approach for PDAC [135].…”

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“…Furthermore, in AsPC-1 subcutaneous xenografts, MPT0E028 and PD98059 combination revealed enhanced antitumor activity (63). Recently, MEK inhibitor mirdametinib (PD0325901) exerted antitumor efficacy in MIA PaCa-2 PDAC xenografts at day 4 and became refractory within a week after treatment due to the involvement of clusterin expression (64). SCH772984 was the first ERK inhibitor studied in PDAC, and it displayed the ability to suppress PDAC xenograft growth (27).…”