Drug-driven reclassification of multiple tumour subtypes reveals intrinsic molecular concordance of therapy across histologically disparate cancers

Cancers that are histologically defined as the same type of cancer often need a distinct therapy based on underlying heterogeneity; likewise, histologically disparate cancers can require similar treatment approaches due to intrinsic similarities. A comprehensive analysis integrated with drug response data and genomic alterations, particularly to reveal therapeutic concordance mechanisms across histologically disparate tumour subtypes, has not yet been fully exploited. In this study, we used pharmacogenomic profiling data provided from the Cancer Genome Project (CGP) in a systematic in silico investigation of the pharmacological subtypes of cancers and the intrinsic concordance of molecular mechanisms leading to similar therapeutic responses across histologically disparate tumour subtypes. We further developed a novel approach to redefine cell-to-cell similarity and drug-to-drug similarity from the therapeutic concordance, providing a new point of view to study cancer heterogeneity. Our study identified that histologically different tumours, such as malignant melanoma and colorectal adenocarcinoma, could belong to the same pharmacological subtype regarding drug sensitivity to MEK inhibitors, which was determined by their genomic alterations, high occurrence of BRAF or KRAS mutations. Therapeutic concordance for chemotherapy drugs was identified across histologically disparate hematological tumors mainly due to the extraordinary activation of the cell cycle in blood cancers. A subcluster of SCLC had a more similar profile with hematological tumors, and was associated with the malignant phenotype, with a higher level of MYC expression. We developed a website to store and visualize the pharmacological subtypes of drugs, as well as their connected genomic and expression alterations. ### Competing Interest Statement The authors have declared no competing interest. * ACC : Adrenocortical carcinoma ALL : Acute lymphoblastic leukemia BLCA : Bladder urothelial carcinoma BRCA : Breast invasive carcinoma CESC : Cervical squamous cell carcinoma and endocervical adenocarcinoma CLL : Chronic lymphocytic leukemia COREAD : Colon adenocarcinoma and rectum adenocarcinoma DLBC : Lymphoid neoplasm diffuse large B-cell Lymphoma ESCA : Esophageal carcinoma GBM : Glioblastoma multiforme HNSC : Head and neck squamous cell carcinoma KIRC : Kidney renal clear cell carcinoma LAML : Acute myeloid leukemia LCML : Chronic myelogenous leukemia LGG : Brain lower grade glioma LIHC : Liver hepatocellular carcinoma LUAD : Lung adenocarcinoma LUSC : Lung squamous cell carcinoma MB : Medulloblastoma MESO : Mesothelioma MM : Multiple myeloma NB : Neuroblastoma OV : Ovarian serous cystadenocarcinoma PAAD : Pancreatic adenocarcinoma PRAD : Prostate adenocarcinoma SCLC : Small cell lung cancer SKCM : Skin cutaneous melanoma STAD : Stomach adenocarcinoma THCA : Thyroid carcinoma UCEC : Uterine corpus endometrial carcinoma CGP : The Cancer Genome Project IC50 : Half maximal inhibitory concentration TCGA : The Cancer Genome Atlas Program FDA : U.S. Food and Drug Administration RTK : Receptor tyrosine kinase MEK : Mitogen-activated protein kinase kinase