DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition.

Elisa Izquierdo,Chris Jones,Thomas S Jacques,Michael Hubank,Richard G Grundy,Jessica K.R Boult,Mark Stubbs,Jacques Grill,Giulia Pericoli,Susan Picton,Matthew Clarke,Alan Mackay,Amy R Fairchild,Lu Yu,Jenny Adamski,Sarita Depani,Valeria Molinari,Georgia Roumelioti,Simon P Robinson,Shaun Wilson,Bassel Zebian,Elisabet Fernandez,Fernando Carceller,Maria Vinci,Sara Temelso,Darren Hargrave,Lynley V Marshall,Lisa Howell,Molina Das,Yura Grabovska,Maria Antonietta Ajmone‐Cat ,Patricia O’hare ,Jyoti Choudhary ,Paula Proszek ,Rebecca Rogers ,Diana Carvalho ,Juliet Gray

doi:10.1158/2159-8290.cd-20-0930

Abstract

We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic. This article is highlighted in the In This Issue feature, p. 587.

Highlights

The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction regulating cell proliferation, differentiation and cell death [1]
We identify specific genetic dependencies associated with response to trametinib in vitro, explore mechanisms of acquired resistance which emerge to single agent targeted therapy which emerge, and present rational drug combinations which may circumvent this in future clinical trials
All H3F3A_K27M and EZHIP cases clustered with other diffuse midline glioma (DMG) K27M tumours, the HIST2H3C_K27M case (ICRB184) was most similar to ICR. We thank Rosemary Burke (ICR)-B118 and other MYCN-amplified glioblastoma in the t-SNE projection of the methylation array data (Figure 1B)

Summary

Introduction

The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction regulating cell proliferation, differentiation and cell death [1]. MAPK pathway alterations are commonly found in childhood cancer, brain tumours, and especially low and high-grade gliomas [5] These include pilocytic astrocytoma (KIAA1549:BRAF tandem duplication, RAF fusions, NF1, FGFR1, BRAF_V600E) [6,7], mixed glioneuronal tumours (FGFR1, BRAF_V600E, KIAA1549:BRAF) [8,9,10], pleomorphic xanthoastrocytomas (BRAF_V600E) [11,12], infant pHGG (NTRK1/2/3, ROS1, ALK, MET fusions) [13,14,15], non-brainstem pHGG (FGFR1, NF1, BRAF_V600E, NTRK2_ITD, MET) [13,16,17,18] and DIPG (PIK3R1, NF1) [13,19]. With a median survival of 9-12 months [20], they represent an unexplored option in a tumour type in desperate need of novel treatment strategies [21]

Methods

Results

Conclusion