New hopes in the fight against cancer: a special issue on targeted anti-cancer drug discovery and cell signaling.

Since the declaration of war on cancer more than 40 years ago, progresses on cancer treatment outcomes have been slow and limited for most part, despite major investments in research and development. However, the realization that cancer is an extremely complex and heterogeneous mixture of diseases, coupled with technological advances in cancer genomics, proteomics, and metabolomics, has led to the development of novel and more effective treatment approaches in recent years. In fact, the approvals of multiple new classes of targeted therapies , particularly anti-cancer immune therapy agents in recent months, may have signaled the arrival of a new era in our fights with cancer. With the expansion of anti-cancer therapeutics toolbox, it is now possible to design individualized treatments to match the genetic makeups of the patients and their tumors. It is fair to say that there is no better time than now for cancer research. This special issue showcases 11 up-to-date reviews written by experts in their corresponding fields covering the major forefronts of targeted cancer drug discovery research. As the most mutated oncogene in human cancers and one of the first oncogenes discovered, rat sarcoma viral oncogene homolog (RAS) is the 800-pound gorilla. Despite more than three decades of extensive research and development efforts, attempts to develop thera-peutics targeting RAS have not been successful, which leads to the perception that RAS is 'undruggable'. Driven by a better understanding of RAS signaling networks and the advent of novel chemical biology approaches, the RAS research field is undergoing a renaissance. Therefore , it is not surprising that we have four review articles covering different aspects of recent developments in targeting this 'undruggable' cancer villain. The extreme high affinity for ligand and similarity of the ligand binding sites among large numbers of small GTPases pose major challenges to develop direct RAS inhibitors. Innovative and un-conventional approaches are required to overcome this major barrier. While McCarthy et al. [1] discuss recent progresses in applying structure-based computational approaches to search for novel allo-steric ligand binding sites on the soluble and membrane-bound RAS, Deng and colleagues [2] review different strategies, including an intriguing and alternative concept of hyperactivating KRAS by activators, currently being explored to target cancer activating KRAS in non-small-cell lung cancer (NSCLC). On the other hand, Lv et al. [3] examine the potential of targeting the metabolic reprogramming driven by oncogenic RAS. Whether these novel approaches and concepts will lead to …