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Precision oncology probe set for nomination of biomarker driven intervention opportunities in lung cancer

ABSTRACT: Diversity in the genetic lesions that drive cancer initiation and progression is extreme. In consequence, a pressing challenge is the development of pharmaceuticals that selectively target disease mechanisms within the appropriate cancer patients. To help delineate the landscape of opportunities that can address this challenge, we have employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. To do this, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cell models representative of the somatic lesions detected in lung cancer. 171 distinct chemical/genetic associations, exploiting disease-selective mechanistic vulnerabilities within a diverse array of biological systems, were discovered. These corresponded to both novel and known oncogenotypes detectable within significant patient populations that lack effective therapy. Chemically addressab le addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer. One chemical in the screen corrected with high expression levels of the positive regulator of the TLR pathway, PELI2, and high expression of PELI2 was predictive of chemical sensitivities outside the training set. SW151511 was thus selected for delineation of global changes in gene expression pattern in response to chemical perturbation. In this experiment, two SW151511-sensitive cells (H596 and H2122) and two SW151511-resistant cells (H661, HCC366) were treated for 24 hours with 10 uM of either chemical or DMSO. After which, microarray expression profiles were determined using Illumina BeadArray V4 and normalized with lumi in R bioconductor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104757 | GEO | 2018/08/09

REPOSITORIES: GEO

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Project description:Altered metabolism is an important part of malignant transformation of tumor cells. Oncogenic transformation may reprogram tumor metabolism and render tumor cells addicted to extracellular nutrients. Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear-cell renal cancer cells (ccRCC) with or without VHL upon the deprivation of individual amino acids. We identified that cystine deprivation triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts. Similar cystine addiction was also observed in VHL-deficient primary RCC tumors cells. Blockage of cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status. Therefore, metabolic differences due to cystine deprivation are not different enough to readily explain the distinct fate of life vs. death in VHL-deficient and restored cell.. Instead, we found that increased levels of TNFÎ± associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFÎ± in the VHL-deficient ccRCC renders these cells susceptible to the necrosis signaling triggered by cystine deprivation. In addition, we identified that cystine-deprived necrosis in VHL-deficient RCC depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFÎ±-RIP1/3-MLKL necrosis pathways that culminate in MLKL oligomerization and programmed necrosis. Together, our data reveal that the contextual cystine-addictions in VHL-deficient ccRCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis. RNA was extracted by RNAeasy kits (Qiagen) from the RCC4 Vec and VHL-reconstituted cells which were exposed to the control full DMEM or cystine deprived DMEM media for 6 hours (three replicates in each condition).

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Precision oncology probe set for nomination of biomarker driven intervention opportunities in lung cancer

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