Targeting vulnerabilities in IDH mutant tumours: The model matters

Introduction Synthetic lethal interactions with IDH1 and IDH2 (IDH) mutations were identified in non-endogenous IDH mutant (IDH MUT ) AML and glioma models, but are absent in endogenous IDH MUT chondrosarcoma cell lines. The translation into successful clinical applications has remained challenging, implying artificially created models do not fully recapitulate endogenous IDH MUT tumour biology. The aim of this study was to elucidate if the model system is indeed an important factor to consider when studying therapeutic vulnerabilities in IDH MUT tumours. Methods Vector-based and CRISPR-Cas9 approaches were used to introduce or revert the IDH1 mutation in chondrosarcoma cell lines. These isogenic cell line pairs were used to examine the presence of known therapeutic vulnerabilities and their underlying biological mechanisms. Results Vector-based IDH MUT chondrosarcoma models showed the previously reported synthetic lethal interactions, but these treatment sensitivities were absent in the CRISPR-edited models. Interestingly, not all vector-based IDH MUT cell lines displayed the same therapeutic vulnerabilities. Differences in treatment response were associated with multiple factors, including IDH MUT protein expression and D-2-HG levels, in line with the fact that therapeutic vulnerabilities could be induced in the CRISPR-edited models by enhancing D-2-HG levels. Conclusion Our findings demonstrate that synthetic lethal interactions observed in vector-based models are often a consequence of IDH MUT protein overexpression and supra-physiological D-2-HG levels. These results highlight that relying on artificially created IDH MUT models may lead to the identification of therapeutic vulnerabilities that are not present in IDH MUT tumours, potentially explaining the poor translation of preclinical findings to clinical trials.