Background Anti-cancer cytotoxic treatments like platinum-derived compounds often show low therapeutic efficacy, high-risk side effects and resistance. Hence, targeted treatments designed to attack only tumour cells avoiding these harmful side effects are highly needed in clinical practice. Due to this, precision oncology has arisen as an approach to specifically target alterations present only in cancer cells, minimising side effects for patients. It involves the use of molecular biomarkers present in each kind of tumour for diagnosis, prognosis and treatment. Since these biomarkers are specific for each cancer type, physicians use them to stratify, diagnose or take the best therapeutic options for each patient depending on the features of the specific tumour. Aim This review aims to describe the current situation, limitations, advantages and perspectives about precision oncology in Latin America. Main body For many years, many biomarkers have been used in a clinical setting in developed countries. However, in Latin American countries, their broad application has not been affordable partially due to financial and technical limitations associated with precarious health systems and poor access of low-income populations to quality health care. Furthermore, the genetic mixture in Latin American populations could generate differences in treatment responses from one population to another (pharmacoethnicity) and this should be evaluated before establishing precision therapy in particular populations. Some research groups in the region have done a lot of work in this field and these data should be taken as a starting point to establish networks oriented to finding clinically useful cancer biomarkers in Latin American populations. Conclusion Latin America must create policies allowing excluded populations to gain access to health systems and next generation anti-cancer drugs, i.e. high-cost targeted therapies to improve survival. Also, cancer clinical research must be oriented to establish cancer biomarkers adapted to specific populations with different ethnicity, allowing the improvement of patient outcomes.

BackgroundThe metabolic inhibitor 3-bromopyruvate (3-BrPA) is a promising anti-cancer alkylating agent, shown to inhibit growth of some colorectal carcinoma with KRAS mutation. Recently, we demonstrated increased resistance to 3-BrPA in wt p53 tumor cells compared to those with p53 silencing or mutation. Since hypoxic microenvironments select for tumor cells with diminished therapeutic response, we investigated whether hypoxia unequally increases resistance to 3-BrPA in wt p53 MelJuso melanoma harbouring (Q61L)-mutant NRAS and wt BRAF, C8161 melanoma with (G12D)-mutant KRAS (G464E)-mutant BRAF, and A549 lung carcinoma with a KRAS (G12S)-mutation. Since hypoxia increases the toxicity of the p53 activator, Prima-1 against breast cancer cells irrespective of their p53 status, we also investigated whether Prima-1 reversed hypoxic resistance to 3-BrPA.ResultsIn contrast to the high susceptibility of hypoxic mutant NRAS MelJuso cells to 3-BrPA or Prima-1, KRAS mutant C8161 and A549 cells revealed hypoxic resistance to 3-BrPA counteracted by Prima-1. In A549 cells, Prima-1 increased p21CDKN1mRNA, and reciprocally inhibited mRNA expression of the SLC2A1-GLUT1 glucose transporter-1 and ALDH1A1, gene linked to detoxification and stem cell properties. 3-BrPA lowered CAIX and VEGF mRNA expression. Death from joint Prima-1 and 3-BrPA treatment in KRAS mutant A549 and C8161 cells seemed mediated by potentiating oxidative stress, since it was antagonized by the anti-oxidant and glutathione precursor N-acetylcysteine.ConclusionsThis report is the first to show that Prima-1 kills hypoxic wt p53 KRAS-mutant cells resistant to 3-BrPA, partly by decreasing GLUT-1 expression and exacerbating pro-oxidant stress.

Establishing the KRAS mutational status of tumor samples is essential to manage patients with colorectal or lung cancer, since these mutations preclude treatment with monoclonal anti-epidermal growth factor receptor (EGFR) antibodies. We report an inexpensive, rapid multiplex allele-specific qPCR method detecting the 7 most clinically relevant KRAS somatic mutations with concomitant amplification of non-mutated KRAS in tumor cells and tissues from CRC patients. Positive samples evidenced in the multiplex assay were further subjected to individual allele-specific analysis, to define the specific mutation. Reference human cancer DNA harbouring either G12A, G12C, G12D, G12R, G12S, G12V and G13D confirmed assay specificity with ≤1% sensitivity of mutant alleles. KRAS multiplex mutation analysis usefulness was also demonstrated with formalin-fixed paraffin embedded (FFPE) from CRC biopsies. Conclusion. Co-amplification of non-mutated DNA avoided false negatives from degraded samples. Moreover, this cost effective assay is compatible with mutation detection by DNA sequencing in FFPE tissues, but with a greater sensitivity when mutant DNA concentrations are limiting.

Ammonium tetrathiomolybdate (TTM) and disulfiram (DSF) are copper (Cu) chelators in cancer clinical trials partly because Cu chelation: a) restricts the activity of Cu-binding MEK1/2 enzymes which drive tumourigenesis by KRAS or BRAF oncogenic mutations and b) enhances uptake of oxaliplatin (OxPt), clinically used in advanced KRAS-mutant colorectal carcinomas (CRC). Whereas TTM decreases intracellular Cu trafficking, DSF can reach other Cu-dependent intracellular proteins. Since the use of individual or combined Cu chelation may help or interfere with anti-cancer therapy, this study investigated whether TTM modifies the response to DSF supplemented with: 1) UO126, a known MEK1/2 inhibitor; 2) other Cu chelators like neocuproine (NC) or 1, 10-o-phenanthroline (OPT) in wt p53 melanoma cells differing in BRAF or KRAS mutations; 3) OxPt in mutant p53 CRC cells devoid of KRAS and BRAF mutations or harbouring either KRAS or BRAF mutations. TTM was not toxic against V600E-mut-BRAF A375 and G12D-mut-KRAS/high c-myc C8161 melanoma cells. Moreover, TTM protected both melanoma types from toxicity induced by DSF, NC and co-treatment with sub-lethal levels of DSF and the MEK inhibitor, UO126. Toxicity by co-treatment with DSF+OPT was poorly reversed by TTM in C8161 melanoma cells. In contrast to the greater toxicity of 0.1 μM DSF against mutant p53 CRC cells irrespective of their KRAS mutation, TTM did not protect G12V-mut-KRAS/high c-myc SW620 CRC from DSF+OxPt compared to KRAS-WT/BRAF-WT Caco-2 CRC. Our results show that DSF co-treatment with: a) MEK inhibitors may enhance tumour suppression; b) OxPt in CRC may counteract impaired response to cetuximab by KRAS/BRAF mutations and c) as a single treatment, TTM may be less effective than DSF and decreases the efficacy of the latter.HighlightsPotentiation of melanoma antitumour toxicity of DSF by MEK inhibitor is reversed by TTM.KRAS/c-MYC dysregulation attenuates TTM reversion of melanoma toxicity by DSF + OPT.KRAS/c-MYC dysregulation increases melanoma NC toxicity reversed by TTM.BRAF mutation and lower c-MYC may attenuate toxicity by DSF ± OxPt in colorectal cancer cells

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