Machine learning models to predict in vivo drug response via optimal dimensionality reduction of tumour molecular profiles

Abstract

Inter-tumour heterogeneity is one of cancers most fundamental features. Patient stratification based on drug response prediction is hence needed for effective anti-cancer therapy. However, lessons from the past indicate that single-gene markers of response are rare and/or often fail to achieve a significant impact in clinic. In this context, Machine Learning (ML) is emerging as a particularly promising complementary approach to precision oncology. Here we leverage comprehensive Patient-Derived Xenograft (PDX) pharmacogenomic data sets with dimensionality-reducing ML algorithms with this purpose. Results show that combining multiple gene alterations via ML leads to better discrimination between sensitive and resistant PDXs in 19 of the 26 analysed cases. Highly predictive ML models employing concise gene lists were found for three cases: Paclitaxel (breast cancer), Binimetinib (breast cancer) and Cetuximab (colorectal cancer). Interestingly, each of these ML models identify some responsive PDXs not harbouring the best actionable mutation for that case (such PDXs were missed by those single-gene markers). Moreover, ML multi-gene predictors generally retrieve a much higher proportion of treatment-sensitive PDXs than the corresponding single-gene marker. As PDXs often recapitulate clinical outcomes, these results suggest that many more patients could benefit from precision oncology if multiple ML algorithms were applied to existing clinical pharmacogenomics data, especially those algorithms generating classifiers combining data-selected gene alterations.