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Introduction: The latest GLOBOCAN 2021 reports that colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Most CRC cases are sporadic and associated with several risk factors, including lifestyle habits, gut dysbiosis, chronic inflammation, and oxidative stress., Aim: To summarize the biology of CRC and discuss current therapeutic interventions designed to counteract CRC development and to overcome chemoresistance., Methods: Literature searches were conducted using PubMed and focusing the attention on the keywords such as "Current treatment of CRC" or "chemoresistance and CRC" or "oxidative stress and CRC" or "novel drug delivery approaches in cancer" or "immunotherapy in CRC" or "gut microbiota in CRC" or "systematic review and meta-analysis of randomized controlled trials" or "CSCs and CRC". The citations included in the search ranged from September 1988 to December 2022. An additional search was carried out using the clinical trial database., Results: Rounds of adjuvant therapies, including radiotherapy, chemotherapy, and immunotherapy are commonly planned to reduce cancer recurrence after surgery (stage II and stage III CRC patients) and to improve overall survival (stage IV). 5-fluorouracil-based chemotherapy in combination with other cytotoxic drugs, is the mainstay to treat CRC. However, the onset of the inherent or acquired resistance and the presence of chemoresistant cancer stem cells drastically reduce the efficacy. On the other hand, the genetic-molecular heterogeneity of CRC often precludes also the efficacy of new therapeutic approaches such as immunotherapies. Therefore, the CRC complexity made of natural or acquired multidrug resistance has made it necessary the search for new druggable targets and new delivery systems., Conclusion: Further knowledge of the underlying CRC mechanisms and a comprehensive overview of current therapeutic opportunities can provide the basis for identifying pharmacological and biological barriers that render therapies ineffective and for identifying new potential biomarkers and therapeutic targets for advanced and aggressive CRC., Competing Interests: The authors declare that the review was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tirendi, Marengo, Domenicotti, Bassi, Almonti and Vernazza.)

Background: Malignant melanoma is the most lethal form of skin cancer which shows BRAF mutation in 50% of patients. In this context, the identification of BRAF V600E mutation led to the development of specific inhibitors like PLX4032. Nevertheless, although its initial success, its clinical efficacy is reduced after six-months of therapy leading to cancer relapse due to the onset of drug resistance. Therefore, investigating the mechanisms underlying PLX4032 resistance is fundamental to improve therapy efficacy. In this context, several models of PLX4032 resistance have been developed, but the discrepancy between in vitro and in vivo results often limits their clinical translation., Methods: The herein reported model has been realized by treating with PLX4032, for six months, patient-derived BRAF-mutated melanoma cells in order to obtain a reliable model of acquired PLX4032 resistance that could be predictive of patient's treatment responses. Metabolic analyses were performed by evaluating glucose consumption, ATP synthesis, oxygen consumption rate, P/O ratio, ATP/AMP ratio, lactate release, lactate dehydrogenase activity, NAD + /NADH ratio and pyruvate dehydrogenase activity in parental and drug resistant melanoma cells. The intracellular oxidative state was analyzed in terms of reactive oxygen species production, glutathione levels and NADPH/NADP + ratio. In addition, a principal component analysis was conducted in order to identify the variables responsible for the acquisition of targeted therapy resistance., Results: Collectively, our results demonstrate, for the first time in patient-derived melanoma cells, that the rewiring of oxidative phosphorylation and the maintenance of pyruvate dehydrogenase activity and of high glutathione levels contribute to trigger the onset of PLX4032 resistance., Conclusion: Therefore, it is possible to hypothesize that inhibitors of glutathione biosynthesis and/or pyruvate dehydrogenase activity could be used in combination with PLX4032 to overcome drug resistance of BRAF-mutated melanoma patients. However, the identification of new adjuvant targets related to drug-induced metabolic reprogramming could be crucial to counteract the failure of targeted therapy in metastatic melanoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Garbarino, Valenti, Monteleone, Pietra, Mingari, Benzi, Bruzzone, Ravera, Leardi, Farinini, Vernazza, Grottoli, Marengo and Domenicotti.)