Somatic Loss of Wild-Type Kras Enhances Cancer Fitness and Promotes MEK Dependence
UID: 10682
- Description
- Summary from the GEO: "Investigating therapeutic “outliers” that show exceptional responses to anti-cancer treatment can reveal unexpected synthetic lethal interactions and uncover biomarkers of drug sensitivity. Preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D “knock-in” mice showed that the MEK inhibitor PD0325901 (PD901) extended survival while the pan-phosphoinositide 3-kinase (PI3K) inhibitor GDC-0941 was ineffective. One outlier PD901-treated AML had a four-fold improvement in survival, and exhibited intrinsic drug resistance at relapse. This resistant leukemia arose from an evolutionary precursor of the dominant drug-sensitive AML, and KrasG12D was duplicated in both AML clones. Loss of wild-type (WT) Kras both enhanced the competitive fitness of the dominant clone and rendered it more sensitive to MEK inhibition. Similarly, colorectal cancer cell lines with loss of WT KRAS are more sensitive to MEK inhibitors, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized a heterozygous mutant HCT116 cells to drug treatment. In a large prospectively characterized cohort of tumors from patients with advanced and metastatic cancers, 642 of 1168 (55%) with KRAS mutations exhibited allelic imbalance. Together, these studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer, and can modulate competitive fitness and MEK dependency.
Total bone marrow was harvested from secondary transplant recipient mice, subjected to red blood cell lysis, and total RNA was harvested using the RNeasy mini kit (Qiagen) and hybridized to a Gene 1.0 ST array (Affymetrix) according to the manufacturer's instructions. Sensitive and resistant specimens were run in triplicate. Raw data were processed with aroma.affymetrix (Bengtsson et al., 2008) and background corrected with RMA followed by quantile normalization and summarization using the RMA probe-level model (PLM) to obtain gene-level summaries. Statistically significant differential expression between sensitive and resistant cells was determined with a moderated empirical Bayes approach (Smyth, 2004) and multiple hypothesis correction was performed. Significant genes were those with a False Discovery Rate (FDR) of
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Access via GEO
Raw, CEL, and CHP sequencing data.
Accession #: GSE92682Access via BioProjectAdditional information about overall initiative.
Accession #: PRJNA358327 - Access Restrictions
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Free to All
- Access Instructions
- The NCBI Gene Expression Omnibus, SRA, and BioProject databases provide open access to these files.
- Associated Publications
- Data Type
- Equipment Used
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[MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [transcript (gene) version]
- Dataset Format(s)
- TAR, CEL, RAW, CHP
- Dataset Size
- 25.5 Mb (TAR [of CEL, CHP] )
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