2022 LCRF–ALK Positive Research Grant
Álvaro Villalonga, PhD
Memorial Sloan-Kettering Cancer Center
Research Project:
Identifying epigenomic mechanisms of ALK TKI resistance
Summary:
ALK inhibitors are very effective in the treatment of ALK fusion-positive tumors, but these eventually develop resistance to therapy. Understanding how tumors become resistant is key to identify subsequent therapeutic approaches that will extend treatment efficacy. Most of what we know about treatment resistance in this setting is limited to how some of these tumors develop other changes in the ALK gene itself or other genes (mutations). However, other tumors may become resistant through a different way, by undergoing major shifts in which genes are active (“epigenetic” changes). We seek to characterize these changes and develop new therapeutic strategies for those patients with ALK fusion-positive lung cancers whose tumors develop this type of resistance.
Final report:
Submitted by Esther Redin, PhD, co-grantee
134 clinical specimens including 88 naïve tumors and 45 ALK TKI-treated tumors were collected. ALK TKI-resistant tumors (both untreated and treated) exhibited a significant upregulation of cell cycle, DNA replication, DNA repair, EMT, and TGF-ß-related pathways, while MAPK and histone deacetylation pathways were downregulated. RNAseq was performed to identify new cell subpopulations. Minimal residual disease (MRD) tumors showed an enrichment of new clusters not detected in vehicle tumors and resistant tumors exhibited an enrichment of clusters found at low percentages in both vehicle and MRD tumors. Lx866, the first human model of histological transformation in the ALK fusion setting, has been identified. In the original PDX displaying a poorly differentiated lung adenocarcinoma phenotype, some cells were already expressing these markers, potentially indicating the onset of histological transformation. Pathway enrichment analysis confirmed the upregulation of MYC suggesting that this may be a mechanism of resistance. Simurosertib suppressed the expression of MYC in resistant versus sensitive tumors in the clinical RNA-seq data. These results suggest that a subset of ALK-fusion patients may benefit from this combination therapy.
Impact:
Despite major treatment advances in ALK+ NSCLC, the majority of patients are not cured due to the development of treatment resistance. This researcher is examining individual patient tumor samples both before and after treatment to determine mechanisms of resistance. A number of interesting changes have been identified in treatment oof naïve, minimal residual disease before disease progression and resistant tumors. Combination treatment of human cancer derived tumor models using available drugs combined with the ALK inhibitor lorlatinib targeting these individual changes have yielded promising results. The fact that some of these drugs are clinically available make it easy for transitioning to a clinical trial. By understanding causes for resistance and targeting them, informed intelligent approaches to treatment can be designed.