Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia

Abstract

Genetic alterations initiate tumors and enable the evolution of drug resistance. The pro-cancer view of mutations is however incomplete, and several studies show that mutational load can reduce tumor fitness. Given its negative effect, genetic load should make tumors more sensitive to anticancer drugs. Here, we test this hypothesis across all major types of cancer from the Cancer Cell Line Encyclopedia, which provides genetic and expression data of 496 cell lines together with their response to 24 common anticancer drugs. We found that the efficacy of 9 out of 24 drugs showed significant association with genetic load in a pan-cancer analysis. The associations for some tissue-drug combinations were remarkably strong, with genetic load explaining up to 83% of the variance in the drug response. Overall, the role of genetic load depended on both the drug and the tissue type with 10 tissues being particularly vulnerable to genetic load. We also identified changes in gene expression associated with increased genetic load, which included cell-cycle checkpoints, DNA damage and apoptosis. Our results show that genetic load is an important component of tumor fitness and can predict drug sensitivity. Beyond being a biomarker, genetic load might be a new, unexplored vulnerability of cancer.

When Functionalization Becomes Useful: Ionic Liquids with a “Sweet” Appended Moiety Demonstrate Drastically Reduced Toxicological Effects

“…56-57-58 Cancer cells are generally more susceptible to toxicity than normal cells since they have a highly unstable genetic load and undergo rapid cell divisions. 59 The cytotoxic effect of ILs was investigated using the MTT assay. 60 The results, expressed as IC 50 values, were calculated from the dose-response curves.…”

“…All ILs were tested for their cytotoxicity. As stated above, three different human cancer cell lines were chosen as the prototype of human cells, namely, HeLa, HCT-116, and MCF-7, derived from cervical, colon, and breast cancer lines, respectively, and previously used to test IL cytotoxicity. − Cancer cells are generally more susceptible to toxicity than normal cells because they have a highly unstable genetic load and undergo rapid cell divisions …”

Tumor mutational burden and purity adjustment before and after treatment with temozolomide in 27 paired samples of glioblastoma: a prospective study

“…Base composition was based on the UCSC HG19 genome via the BSgenome (BSgenome.Hsapiens.UCSC.hg19) package for R. Mutational signature analysis was performed using the SigFit package [29]. Signature fitting was performed with COSMIC version 3 SBS signatures 1,3,5,8,11,15,16,30, and 40 using the following parameters: iter = 2000, warmup = 1000, chains = 1, seed = 1756, hpd_prob=0.9). Signatures with a lower highest-posterior-density bound greater than 0.01 were considered high confidence.…”

“…All patients with three surgical procedures presented with mutations private for the relapse, suggesting ongoing mutagenesis. We next investigated single-base substitution signatures using a curated set of mutation signatures previously published in GBM ( SBS 1,3,5,8,11,15,16,30,and 40) made available by the Catalogue of Somatic Mutations in Cancer (COSMIC) (Figure 4B). Signature 1 (SBS1), which is associated with spontaneous deamination of 5-methylcytosine…”

“…In this context, TMB is often defined as the number of nonsynonymous somatic mutations in a tumor sample, and high rates of TMB are associated with genome instability, a hallmark of cancer [1]. A high TMB can cause an increased number of neoantigens that serve to recruit the adaptive immune system and as such, provides a potential biomarker for IT response [2] Good clinical response rates have been shown in TMB-high tumors like melanoma, non-small-cell lung cancer (NSCLC), and mismatch repair (MMR) deficient colon cancer [3][4][5][6]. Mutations in melanoma and NSCLC are mainly caused by exogenous mutagenesis and have a TMB-average of 3-400/Megabase (Mb) (range to more than 1000) [7].…”