American Association for Cancer Research
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15357163mct190045-sup-215350_3_supp_5921979_q1mxck.pptx (2.17 MB)

Figure S1 from Genetic Interactions and Tissue Specificity Modulate the Association of Mutations with Drug Response

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posted on 2023-04-03, 15:25 authored by Dina Cramer, Johanna Mazur, Octavio Espinosa, Matthias Schlesner, Daniel Hübschmann, Roland Eils, Eike Staub

The interaction of BRAF and TP53 mutations is associated with resistance to the BRAF inhibitors Dabrafenib and PLX4720. Observed response to A) Dabrafenib in the GDSC and B) the CTRP dataset, and C) PLX4720 in the GDSC and D) the CTRP dataset. Shown cancer cell lines are stratified by tissue and by mutation status of BRAF and TP53. The abbreviation "haematopoietic/ lymphoid" refers to "haematopoietic_and_lymphoid_tissue". Related to Figure 4.

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ARTICLE ABSTRACT

In oncology, biomarkers are widely used to predict subgroups of patients that respond to a given drug. Although clinical decisions often rely on single gene biomarkers, machine learning approaches tend to generate complex multi-gene biomarkers that are hard to interpret. Models predicting drug response based on multiple altered genes often assume that the effects of single alterations are independent. We asked whether the association of cancer driver mutations with drug response is modulated by other driver mutations or the tissue of origin. We developed an analytic framework based on linear regression to study interactions in pharmacogenomic data from two large cancer cell line panels. Starting from a model with only covariates, we included additional variables only if they significantly improved simpler models. This allows to systematically assess interactions in small, easily interpretable models. Our results show that including mutation–mutation interactions in drug response prediction models tends to improve model performance and robustness. For example, we found that TP53 mutations decrease sensitivity to BRAF inhibitors in BRAF-mutated cell lines and patient tumors, suggesting a therapeutic benefit of combining inhibition of oncogenic BRAF with reactivation of the tumor suppressor TP53. Moreover, we identified tissue-specific mutation–drug associations and synthetic lethal triplets where the simultaneous mutation of two genes sensitizes cells to a drug. In summary, our interaction-based approach contributes to a holistic view on the determining factors of drug response.