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Supplementary Data from Combined MEK and PI3K/p110β Inhibition as a Novel Targeted Therapy for Malignant Mesothelioma Displaying Sarcomatoid Features

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posted on 2023-03-31, 03:29 authored by Miriam Marqués, Robin Tranchant, Blanca Risa-Ebrí, María L. Suárez-Solís, Luis C. Fernández, Enrique Carrillo-de-Santa-Pau, Natalia del Pozo, Jaime Martínez de Villarreal, Clément Meiller, Yves Allory, Yuna Blum, Christine Pirker, Balazs Hegedus, Simon T. Barry, Amancio Carnero, Walter Berger, Didier Jean, Francisco X. Real

This file contains Supplementary Material and Methods. Supplementary Table S1 summarizes the antibodies used for IHC and WB; Supplementary Table S2 shows the primers and the shRNAs sequences used; Supplementary Table S3 shows the Selumetinib and AZD8186 concentration ranges used for in vitro experiments; Supplementary Table S4. Summary of patient and tumor characteristics corresponding to the TMA from each institution; Supplementary Table S5. Drug sensitivity values for Selumetinib/AZD8186 responder cells. Supplementary Figure S1. Histology of the metastases of Pten;Trp53-null mouse tumors. Representative H&E staining of kidney, spleen and pancreas metastases of Pten;Trp53-null tumors. Scale bar 200µm (right panels) and 50µm (left panels). Supplementary Figure S2. Signaling analysis of Pten;Trp53-null and Pik3ca*;Trp53-null mouse tumors. Supplementary Figure S3. Characterization of cell lines derived from Pten;Trp53-null and Pik3ca*;Trp53-null tumors. Supplementary Figure S4. Effect of MEK and p110b inhibitors on signaling in Pten;Trp53-null and Pik3ca*;Trp53-null cells. Supplementary Figure S5. A fraction of Selumetinib/AZD8186 treated mice had no macroscopically detectable tumors at autopsy. Supplementary Figure S6. Analysis of synergy between Selumetinib and AZD8186 in the extended panel of primary human PMM cells. Supplementary Figure S7. Comparison of the response of human Pl-MM cultures to the Selumetinib/AZD8186 combination compared to cisplatin. Viability of primary human PMM cells after 72h exposure to serial dilutions of cisplatin or constant ratio combination of Selumetinib/AZD8186. Compound concentration range: 0.025-20µM for Selumetinib and AZD8186 and 1.25-40 µM for cisplatin. The combination ratios for Selumetinib and AZD8186 in each specific culture are specified in Supplementary table S3. Mean+ SEM (n=2-3).

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Asociación Española Contra el Cáncer

ISCIII

Instituto de Salud Carlos III

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ARTICLE ABSTRACT

Among malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to nonepithelioid MM development. In Pten;Trp53-null mice developing MM, the Gαi2-coupled receptor subunit activated MEK/ERK and PI3K, resulting in aggressive, immune-suppressed tumors. Combined inhibition of MEK and p110β/PI3K reduced mouse tumor cell growth in vitro. Therapeutic inhibition of MEK and p110β/PI3K using selumetinib (AZD6244, ARRY-142886) and AZD8186, two drugs that are currently in clinical trials, increased the survival of Pten;Trp53-null mice without major toxicity. This drug combination effectively reduced the proliferation of primary cultures of human pleural (Pl) MM, implicating nonepithelioid histology and high vimentin, AKT1/2, and Gαi2 expression levels as predictive markers of response to combined MEK and p110β/PI3K inhibition. Our findings provide a rationale for the use of selumetinib and AZD8186 in patients with MM with sarcomatoid features. This constitutes a novel targeted therapy for a poor prognosis and frequently chemoresistant group of patients with MM, for whom therapeutic options are currently lacking. Mesothelioma is highly aggressive; its sarcomatoid variants have worse prognosis. Building on a genetic mouse model, a novel combination therapy is uncovered that is relevant to human tumors.

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