Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers

There are currently no effective targeted therapies for KRAS mutant cancers. Therapeutic strategies that combine MEK inhibitors with agents that target apoptotic pathways may be a promising therapeutic approach. We investigated combining MEK and MDM2 inhibitors as a potential treatment strategy for KRAS mutant non-small cell lung cancers and colorectal carcinomas that harbor wild-type TP53. The combination of pimasertib (MEK inhibitor) + SAR405838 (MDM2 inhibitor) was synergistic and induced the expression of PUMA and BIM, led to apoptosis and growth inhibition in vitro, and tumor regression in vivo. Acquired resistance to the combination commonly resulted from the acquisition of TP53 mutations, conferring complete resistance to MDM2 inhibition. In contrast, resistant clones exhibited marked variability in sensitivity to MEK inhibition, which significantly impacted sensitivity to subsequent treatment with alternative MEK inhibitor-based combination therapies. These results highlight both the potential promise and limitations of combining MEK and MDM2 inhibitors for treatment of KRAS mutant NSCLC and CRC

Reuse-based Online Models for Caches

We develop a reuse distance/stack distance based analytical modeling framework for efficient, online prediction of cache performance for a range of cache configurations and replacement policies LRU, PLRU, RANDOM, NMRU. Our framework unifies existing cache miss rate prediction techniques such as Smith’s associativity model, Poisson variants, and hardware way-counter based schemes. We also show how to adapt LRU way-counters to work when the number of sets in the cache changes. As an example application, we demonstrate how results from our models can be used to select, based on workload access characteristics, last-level cache configurations that aim to minimize energy-delay product. Categories andSubjectDescriptor

Additional file 7: Figure S7. of Unique, dual-indexed sequencing adapters with UMIs effectively eliminate index cross-talk and significantly improve sensitivity of massively parallel sequencing

Multiplex captures have comparable uniformity to individual captures. Uniform coverage enables accurate variant calling with minimal sequencing cost. (PDF 115 kb

Additional file 6: Figure S6. of Unique, dual-indexed sequencing adapters with UMIs effectively eliminate index cross-talk and significantly improve sensitivity of massively parallel sequencing

Schematic of the experiment used to measure adapter contamination and multiplexed capture index hopping. Replicate libraries were prepared using 16 unique dual-matched UMI adapters and enriched with the IDT xGen AML Cancer Panel in pools of 1, 4, 8, and 16. Each multiplexing experiment was sequenced on separate Illumina NextSeq runs. (PDF 819 kb

Additional file 10: Figure S10. of Unique, dual-indexed sequencing adapters with UMIs effectively eliminate index cross-talk and significantly improve sensitivity of massively parallel sequencing

Mutation-specific thresholds provide additional improvements to calling accuracy. (a) Number of false positives from 8-oxoguanine errors are found at low frequencies. (b) Increased minimum variant allele frequency thresholds for 8-oxoguanine mutations improves the positive predictive value (PPV) for rare variants without reducing sensitivity. (PDF 168 kb