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Oncogene-induced stress is a hallmark of solid tumors. To endure stress, tumor cells reprogram bioenergetic circuits and therefore, cellular reprograming pathways are now being targeted in multiple clinical studies. Besides oncogenic stress, an area largely understudied is the stress imposed by alteration of genes located on the same chromosome as oncogenes or tumor suppressors (TS) genes that are gained or lost accidentally. A status-quo in cancer etiology is that out of the thousands of somatic alterations found in a cancer cell, only a few called “driver” alterations (i.e., Oncogene amplification of TS loss) cause the cancer phenotype – the majority of genomic alterations, called “passengers” that are accidentally altered, are believed to be non-significant. Many passenger alterations are damaging to cells but have largely evaded negative selection to change the dynamics of cancer progression. Targeting the in-built vulnerability imposed by passenger alteration, or survival pathways reprogrammed due to passenger alteration may lead to meltdown of certain cancers. Significant amount of cancer genomics data is publicly available. This data is a potential goldmine for new therapeutics. The challenge however, is to drill deep and discover the in-built liabilities of individual cancer types. Through analysis of large public datasets and experimental validation we discovered that the cellular energy sensor AMP kinase is a major regulator of the bioenergetic transcription program in the lethal human brain cancer called glioblastoma. We also identified metabolic genes co-deleted accidentally along with the tumor suppressor PTEN which is lost in about 70% of glioblastoma. Loss of some of these genes imposed significant “hidden” vulnerabilities in PTEN-deleted tumors that were revealed by in-depth molecular analysis. Some of these discoveries may lead to new clinical trials in molecularly stratified glioblastoma patients. |