Search

Summary Novel treatment options for metastatic colorectal cancer (CRC) are urgently needed to improve patient outcome. Here, we screen a library of non-characterized small molecules against a heterogeneous collection of patient-derived CRC spheroids. By prioritizing compounds with inhibitory activity in a subset of—but not all—spheroid cultures, NCT02 is identified as a candidate with minimal risk of non-specific toxicity. Mechanistically, we show that NCT02 acts as molecular glue that induces ubiquitination of cyclin K (CCNK) and proteasomal degradation of CCNK and its complex partner CDK12. Knockout of CCNK or CDK12 decreases proliferation of CRC cells in vitro and tumor growth in vivo. Interestingly, sensitivity to pharmacological CCNK/CDK12 degradation is associated with TP53 deficiency and consensus molecular subtype 4 in vitro and in patient-derived xenografts. We thus demonstrate the efficacy of targeted CCNK/CDK12 degradation for a CRC subset, highlighting the potential of drug-induced proteolysis for difficult-to-treat types of cancer.

Mexico ranks among the 11 major producer countries of minerals worldwide; its open pit and underground systems are 500 years old. This paper presents an overview of the Mexican mining industry from technological development, historical and economic perspectives. The efforts made by mining companies to address issues of environmental management and sustainable development expressed in national and international frameworks, as well as the Mexican environmental regulatory framework for the mining sector, are analyzed. Since, among others, life cycle assessment (LCA) has been recognized as a key topic to promote sustainable development in the Latin American and Caribbean region, this paper also examines the application of LCA in mining. Two life cycle approaches are presented: a national life cycle inventory for base metals, and an integral life cycle model for the management of mining processes.