MEK Inhibition Overcomes Cisplatin Resistance Conferred by SOS/MAPK Pathway Activation in Squamous Cell Carcinoma.

Abstract:

:Genomic analyses of squamous cell carcinoma (SCC) have yet to yield significant strategies against pathway activation to improve treatment. Platinum-based chemotherapy remains the mainstay of treatment for SCC of different histotypes either as a single-agent or alongside other chemotherapeutic drugs or radiotherapy; however, resistance inevitably emerges, which limits the duration of treatment response. To elucidate mechanisms that mediate resistance to cisplatin, we compared drug-induced perturbations to gene and protein expression between cisplatin-sensitive and -resistant SCC cells, and identified MAPK-ERK pathway upregulation and activation in drug-resistant cells. ERK-induced resistance appeared to be activated by Son of Sevenless (SOS) upstream, and mediated through Bim degradation downstream. Clinically, elevated p-ERK expression was associated with shorter disease-free survival in patients with locally advanced head and neck SCC treated with concurrent chemoradiation. Inhibition of MEK/ERK, but not that of EGFR or RAF, augmented cisplatin sensitivity in vitro and demonstrated efficacy and tolerability in vivo. Collectively, these findings suggest that inhibition of the activated SOS-MAPK-ERK pathway may augment patient responses to cisplatin treatment.

journal_name

Mol Cancer Ther

authors

Kong LR,Chua KN,Sim WJ,Ng HC,Bi C,Ho J,Nga ME,Pang YH,Ong WR,Soo RA,Huynh H,Chng WJ,Thiery JP,Goh BC

doi

10.1158/1535-7163.MCT-15-0062

subject

Has Abstract

pub_date

2015-07-01 00:00:00

pages

1750-60

issue

7

eissn

1535-7163

issn

1538-8514

pii

1535-7163.MCT-15-0062

journal_volume

14

pub_type

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