Identification of potential synthetic lethal genes to p53 using a computational biology approach

Abstract

BackgroundIdentification of genes that are synthetic lethal to p53 is an important strategy for anticancer therapy as p53 mutations have been reported to occur in more than half of all human cancer cases. Although genome-wide RNAi screening is an effective approach to finding synthetic lethal genes, it is costly and labor-intensive.MethodsTo illustrate this approach, we identified potentially druggable genes synthetically lethal for p53 using three microarray datasets for gene expression profiles of the NCI-60 cancer cell lines, one next-generation sequencing (RNA-Seq) dataset from the Cancer Genome Atlas (TCGA) project, and one gene expression data from the Cancer Cell Line Encyclopedia (CCLE) project. We selected the genes which encoded kinases and had significantly higher expression in the tumors with functional p53 mutations (somatic mutations) than in the tumors without functional p53 mutations as the candidates of druggable synthetic lethal genes for p53. We identified important regulatory networks and functional categories pertinent to these genes, and performed an extensive survey of literature to find experimental evidence that support the synthetic lethality relationships between the genes identified and p53. We also examined the drug sensitivity difference between NCI-60 cell lines with functional p53 mutations and NCI-60 cell lines without functional p53 mutations for the compounds that target the kinases encoded by the genes identified.ResultsOur results indicated that some of the candidate genes we identified had been experimentally verified to be synthetic lethal for p53 and promising targets for anticancer therapy while some other genes were putative targets for development of cancer therapeutic agents.ConclusionsOur study indicated that pre-screening of potential synthetic lethal genes using gene expression profiles is a promising approach for improving the efficiency of synthetic lethal RNAi screening.

Treatment of Head and Neck Squamous Cell Carcinoma According on the Specific Molecular Features of the Tumor (A Literature Review)

“…В исследованиях установлено увеличение показателей общей выживаемости при применении цетуксимаба, моноклонального антитела против EGFR, в комбина-ции с лучевой терапией или химиотерапией. Тем не ме-нее ответ на цетуксимаб не коррелирует со степенью гиперэкспрессии, и как агент для монотерапии он показывает неутешительные результаты (частота от-вета 6-13 %) [26].…”

“…Также есть данные, что опухолевым и иммунным взаи-модействием объясняется лучший ответ ВПЧ-пози-тивных опухолей. ВПЧ-позитивность ассоциирована с лимфоцитарным ответом, а на животных моделях показано, что иммунокомпетентность -это необхо-димое условие для полного лизиса опухоли [26,33].…”

“…К примеру, ингибирование стрессовой р38-митоген-активированной протеинкиназы MAPKAP kinase 2 (MK2), ATM, SGK2 или PAK3 может увеличить чувствительность опухолевых клеток к химиотерапии (MK2, ATM) и привести к аутофагии (SGK2) или апоп-тозу (PAK3) [25]. Недавний анализ данных идентифи-цировал несколько генов киназ, кандидатов на роли партнеров в реализации механизма синтетической летальности при мутации, -polo-подобную киназу 1, циклинзависимую киназу 1 и aurora-киназу A [26].…”

An Exploration of Mutation Status of Cancer Genes in Breast Cancers

“…Since many kinaseencoding genes have been found to be mutated and upregulated in cancers, development of anticancer drugs that inhibit overexpression of protein kinases has become an active research area in cancer biology [11]. These frequently mutated kinase genes could be potential targets for treatment of breast cancers.…”

“…Therefore, anticancer drugs targeting mutated TP53 are potentially efficacious for a large number of cancer patients. Although mutated TP53 itself is hard to be targeted, its synthetic lethal partners may include promising treatment targets [11].…”