Abstract
dc:description.abstractAnaplastic 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 largely focused on cell line-based models whereby in vitro culture conditions may cause rapid phenotypic and genotypic divergence of patient-derived cells from the originating tumour, we developed two paediatric ALK+ ALCL patient-derived xenograft (PDX) models from liquid biopsy samples of chemotherapy-refractory and crizotinib resistant patients. In vivo investigation showed that second generation ALK inhibitor brigatinib led to a reduction in the mean tumour volume relative to either vehicle or crizotinib treatment. This suggests brigatinib as a treatment option for crizotinib resistant ALCL patients. In summary, this study has identified potential mechanisms of ALK inhibitor resistance particularly in NPM1-ALK positive ALCL and ALK-driven NB.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2020
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Prokoph, Nina
- Advisor dc:contributor.advisor
-
- Turner, Suzanne
Subjects
dc:subject × 10Rights
dc:rightsIdentifiers
dc:identifier.*- Author Identifier
- 0000-0002-8439-4507
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/316435