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Drug-perturbation-based stratification of blood cancer
Sascha Dietrich1,2,3,4, Małgorzata Oleś1, Junyan Lu1
1European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Abstract:
As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
Insights
This study reveals that multiple mutations significantly impact drug responses in blood cancers, particularly chronic lymphocytic leukemia (CLL). Understanding these links aids in personalized cancer therapy and biomarker discovery.
Area of Science:
- Hematology
- Genomics
- Pharmacology
Background:
- The functional impact of genetic mutations on cancer phenotypes and drug response is often unclear.
- Advancements in sequencing reveal extensive mutation repertoires, necessitating a deeper understanding of their therapeutic relevance.
Purpose of the Study:
- To investigate the determinants of drug response in primary blood cancers using multi-omics data.
- To establish a comprehensive data set linking genetic profiles to ex vivo drug sensitivities.
Main Methods:
- Ex vivo drug sensitivity testing of 246 blood cancer samples against 63 drugs.
- Integrated analysis of genome, transcriptome, and DNA methylome data.
- Multivariate modeling to identify key modulators of drug response.
Main Results:
- A primary blood cancer cell encyclopedia revealed disease-specific drug sensitivities.
- In chronic lymphocytic leukemia (CLL), 62% of drug responses correlated with two or more mutations, linking the B cell receptor (BCR) pathway to trisomy 12.
- Phenotypic subgroups based on drug response highlighted dependencies on BCR, mTOR, or MEK signaling, influenced by mutations, gene expression, and methylation.
- Immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 were critical for kinase inhibitor response in CLL.
Conclusions:
- This research challenges the notion that most mutations are functionally irrelevant to cancer drug response.
- The findings support an updated paradigm for understanding tumor biology and have significant implications for biomarker discovery and personalized cancer care.
