KRAS-Mutant Cancers: From Basic Biology to Clinical Translation

Dear Colleagues,

The RAS family of proteins is ubiquitously expressed in mammals and consists of KRAS, NRAS and HRAS isoforms. Among these, KRAS has the highest mutation rate and leads to a poor prognosis of cancer patients. KRAS is most frequently mutated in colorectal carcinoma, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. In addition, KRAS mutations are found in endometrial cancer, biliary tract malignancies, cervical cancer, liver cancer, bladder cancer, breast cancer and myeloid leukaemia. KRAS mutations result in the constitutive activation of KRAS protein that induces pro-proliferative and pro-survival signalling mediated by RAF/MEK/ERK and PI3K/AKT/mTOR, respectively, alter cell metabolism and impact the tumour microenvironment, leading to tumour initiation, progression and metastasis. Given its important role in tumour biology, KRAS is considered a promising drug target in oncology. However, the existence of different KRAS mutations that induce distinct signalling events in cancer renders KRAS signalling highly complex and poses a challenge in cancer treatment, especially considering distinct clinical features of the tumours bearing different KRAS mutations that exert different treatment responses and clinical outcomes. In addition, KRAS mutations co-exist with mutations in other genes such as PIK3CA, APC, EGFR and BRAF, which has important therapeutic and diagnostic implications in cancer. Despite significant progress in recent years in the development of KRAS-mutation-specific inhibitors leading to clinical approval of two KRASG12C inhibitors, Adagrasib and Sotorasib, the emergence of acquired resistance reduces their clinical benefits. For this reason, new combinatorial strategies should be explored to increase the clinical efficacy of KRAS inhibitors and improve the treatment outcomes in KRAS-mutant cancers. This Special Issue welcomes scientific contributions from basic, clinical and translational research that will broaden the current knowledge of the mutant KRAS-driven biology and genetics pertinent to tumour initiation, progression, metastasis and treatment to better understand the molecular and cellular consequences of KRAS mutations in cancer cells, and propose novel strategies to overcome therapeutic resistance in KRAS-mutant cancers.

Dr. Mirela Sedic
Dr. Sérgia Velho
Dr. Luka Bočkor
Guest Editors

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