KRAS was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRAS between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRAS. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRAS-specific inhibitors with promising therapeutic potential.

They have also served as consultants for Kura Oncology, have equity ownership in the company, and are coinventors (along with SK, TW, LS, and PR) on patent applications covering MI-3454 (PCT/US2017/022535). PR is an employee of Kura Oncology, Inc. and has a significant ownership interest in the parent of Wellspring Biosciences, Inc. FB is an employee of Kura Oncology, Inc. Kura Oncology, Inc. and the University of Michigan have filed patent applications covering MI-3454 and they hold intellectual property rights on this compound. OAW has served as a consultant for H3B Biomedicine, Foundation Medicine Inc, Merck, and Janssen, and has received prior research funding from H3B Biomedicine unrelated to the current manuscript. MG receives research support from Cellectis and serves as a consultant in SeqRx.

ObjectiveIn view of the poor prognosis and difficulties in the diagnosis of osteosarcoma, and the functionality of microRNA-Let7A in different types of human cancers, our study aimed to explore the diagnostic and prognostic values of microRNA-Let7A for osteosarcoma.MethodsA total of 39 patients with osteosarcoma and 19 normal healthy people were included in this study. All patients received surgical resection, and tumor tissues as well as pericarcinomatous tissues were collected during surgical operation. Venous blood (2 ml) was extracted from each participant. Expression of microRNA-Let7A in tumor tissues and pericarcinomatous tissues, and expression of E2F2 and microRNA-Let7A in blood of each participant was detected by qRT-PCR. ROC analysis was performed to evaluate the diagnostic values of blood E2F2 and microRNA-Let7A for osteosarcoma, and prognostic values of microRNA-Let7A for osteosarcoma was evaluated by survival curve comparisons.ResultsExpression level of microRNA-Let7A was significantly lower in tumor tissues than that in pericarcinomatous tissues. MicroRNA-Let7A expression in blood was significantly downregulated in osteosarcoma patients compared with normal control. Expression of microRNA-Let7A was negatively correlated with the expression of E2F2 in blood of osteosarcoma patients. Compared with E2F2, blood microRNA-Let7A can more effectively predict osteosarcoma. Overall survival rate of osteosarcoma patient with low blood expression level of miRNA-let-7a was significantly lower than that of patients with high blood expression level of miRNA-let-7a.ConclusionBlood microRNA-Let7A is a promising diagnostic and prognostic biomarker for osteosarcoma.

In conventional milling, appropriate coatings can be used on tools to enhance their cutting performance and efficiency of the production process. In an effort to improve the tooling performance in micro-scale milling, nano-crystalline diamond films were applied on a micro-end mill by a hot filament chemical vapour deposition process. The cutting performance of the nano-crystalline diamond-coated tool, including cutting forces, tool integrity, surface roughness and burr formation, were evaluated in slot milling of aluminium 6061-T6 against that of an uncoated tool in dry cutting conditions. Reduced cutting forces, free chip adhesion, lower tool wear, improved surface roughness, as well as smaller burrs, were observed using the nano-crystalline diamond-coated tool. The investigation illustrates the possibility of applying nanocrystalline diamond coatings on micro-milling tools for dry cutting and better tooling performance.

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