Targeting vulnerabilities in IDH mutant tumours: The model matters

Area of Science:

• Oncology
• Cancer Biology
• Molecular Therapeutics

Background:

• Synthetic lethal interactions are key targets for cancer therapy.
• Previous studies identified synthetic lethality with IDH1 and IDH2 (IDH) mutations in non-endogenous IDH mutant (IDH^MUT) models.
• However, these interactions are absent in endogenous IDH^MUT chondrosarcoma cell lines, suggesting model systems impact therapeutic vulnerability discovery.

Purpose of the Study:

• To investigate the role of model systems in studying therapeutic vulnerabilities in IDH^MUT tumors.
• To determine if artificially created IDH^MUT models accurately reflect endogenous IDH^MUT tumor biology.

Main Methods:

• Generated isogenic chondrosarcoma cell line pairs using vector-based and CRISPR-Cas9 approaches to introduce or revert IDH1 mutations.
• Examined known therapeutic vulnerabilities and their underlying biological mechanisms in these cell lines.

Main Results:

• Vector-based IDH^MUT models exhibited synthetic lethal interactions, while CRISPR-edited models did not.
• Treatment sensitivities varied among vector-based models and correlated with IDH^MUT protein expression and D-2-hydroxyglutarate (D-2-HG) levels.
• Therapeutic vulnerabilities could be induced in CRISPR-edited models by increasing D-2-HG levels.

Conclusions:

• Synthetic lethal interactions in vector-based models are often artifacts of IDH^MUT protein overexpression and supra-physiological D-2-HG levels.
• Relying on artificially created IDH^MUT models can identify non-existent therapeutic vulnerabilities, potentially explaining poor clinical translation of preclinical findings.