ALK in the pathogenesis of cancer
type: CreativeWork
description: Anaplastic Lymphoma Kinase (ALK) has been implicated in the pathogenesis of many types of cancer including Anaplastic Large Cell Lymphoma (ALCL) and neuroblastoma (NB). ALK is an ideal drug target as its endogenous expression is limited to neuronal cells during neonatal development, although resistance to ALK-targeted therapy has been observed. In this thesis I explore potential mechanisms of resistance to the ALK inhibitors that have been approved for ALK+ non-small cell lung cancer (NSCLC) including crizotinib, alectinib, ceritinib, brigatinib and lorlatinib. To define a global landscape of resistance mechanisms, patient-centric studies require many pre- and post-treatment tumour specimens taken from a sufficient number of patients, which is not possible for a rare cancer such as ALK+ ALCL or ALK driven NB. Hence, genome-wide CRISPR overexpression screens were conducted in ALCL and NB cell lines. We show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin-10 receptor alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signalling pathway bypassing otherwise critical phosphorylation of STAT3 by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in paediatric patients suggesting that a combination of crizotinib with chemotherapy could prevent ALK-inhibitor resistance-specific relapse. In the case of ALK-driven NB resistance to ALK inhibition is associated with expression of the serine/threonine-protein kinase PIM1. While both ALK-driven and ALK-negative NB cells were insensitive to several small-molecule pan-PIM kinase inhibitors, knockdown of PIM1 by RNA interference sensitized cells to ALK inhibition and the combination of ALK inhibitors with the PIM1 inhibitor AZD1208 demonstrated mild synergy. Therefore, our data suggest the potential for combined pharmacological inhibition of ALK and PIM1 in patients with ALK-driven NB. Finally, given the above investigations l…
abstract: Anaplastic Lymphoma Kinase (ALK) has been implicated in the pathogenesis of many types of cancer including Anaplastic Large Cell Lymphoma (ALCL) and neuroblastoma (NB). ALK is an ideal drug target as its endogenous expression is limited to neuronal cells during neonatal development, although resistance to ALK-targeted therapy has been observed. In this thesis I explore potential mechanisms of resistance to the ALK inhibitors that have been approved for ALK+ non-small cell lung cancer (NSCLC) including crizotinib, alectinib, ceritinib, brigatinib and lorlatinib. To define a global landscape of resistance mechanisms, patient-centric studies require many pre- and post-treatment tumour specimens taken from a sufficient number of patients, which is not possible for a rare cancer such as ALK+ ALCL or ALK driven NB. Hence, genome-wide CRISPR overexpression screens were conducted in ALCL and NB cell lines. We show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin-10 receptor alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signalling pathway bypassing otherwise critical phosphorylation of STAT3 by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in paediatric patients suggesting that a combination of crizotinib with chemotherapy could prevent ALK-inhibitor resistance-specific relapse. In the case of ALK-driven NB resistance to ALK inhibition is associated with expression of the serine/threonine-protein kinase PIM1. While both ALK-driven and ALK-negative NB cells were insensitive to several small-molecule pan-PIM kinase inhibitors, knockdown of PIM1 by RNA interference sensitized cells to ALK inhibition and the combination of ALK inhibitors with the PIM1 inhibitor AZD1208 demonstrated mild synergy. Therefore, our data suggest the potential for combined pharmacological inhibition of ALK and PIM1 in patients with ALK-driven NB. Finally, given the above investigations l…
author: Prokoph, Nina
language: eng
keywords: CRISPR, Non-Hodgkin Lymphoma, Anaplastic lymphoma kinase, Neuroblastoma, Anaplastic large cell lymphoma, Patient-derived xenograft, Crizotinib, Brigantinib, Resistance, Autoantibody
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/5b5edb37-4735-4391-88c8-07d3046960ce/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2020-08-17
date modified: 2026-07-22T22:24:16Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.63546