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

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posted on 2023-04-03, 14:25 authored by Li Ren Kong, Kian Ngiap Chua, Wen Jing Sim, Hsien Chun Ng, Chonglei Bi, Jingshan Ho, Min En Nga, Yin Huei Pang, Weijie Richard Ong, Ross Andrew Soo, Hung Huynh, Wee Joo Chng, Jean-Paul Thiery, Boon Cher Goh

Supplementary Methods Supplementary Table Captions and legends for Supplementary Figures S1 -S11; Supplementary Table S1: Differentially regulated genes in both cisplatin-resistant and -sensitive phenotypes after cisplatin treatment (fold change > 1.5, P < 0.05); Supplementary Table S2: Baseline characteristics of the head and neck squamous cell carcinoma (HNSCC)population, classified according to the p-ERK1/2 scoring.

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ARTICLE 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. Mol Cancer Ther; 14(7); 1750–60. ©2015 AACR.

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    Molecular Cancer Therapeutics

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    Cell Death And SenescenceEffectors of apoptosisChemotherapyCombination chemotherapyDrug MechanismsCellular responses to anticancer drugsDrug-mediated stimulation of cell death pathwaysDrug ResistanceReversal of drug resistanceSmall Molecule Agents

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