Melanoma onset and progression are associated with a high variety of activating mutations in the MAPK-pathway, most frequently involving BRAF (35-45%) and NRAS (15-25%) genes, but also c-KIT and PTEN. Targeted therapies with BRAF and MEK inhibitors showed promising results over the past years, but it is known that most responses are temporary, and almost all of patients develop a tumor relapse within one year. Different drug-resistance mechanisms underlie the progression of disease and activation of both MAPK and PI3K/AKT/mTOR pathways. Therefore, in this article we reviewed the main studies about clinical effects of several target inhibitors, describing properly the most prominent mechanisms of both intrinsic and acquired resistance. Furthermore, suggestive strategies for overcoming drug resistance and the most recent alternative combination therapies to optimize the use of MAPK pathway inhibitors were also discussed.

Drug–drug interactions (DDIs) can affect both treatment efficacy and toxicity. We used Drug-PIN^® (Personalized Interactions Network) software in colorectal cancer (CRC) patients to evaluate drug–drug–gene interactions (DDGIs), defined as the combination of DDIs and individual genetic polymorphisms. Inclusion criteria were: (i) stage II-IV CRC; (ii) ECOG PS (Performance status sec. Eastern coperative oncology group) ≤2; (iii) ≥5 concomitant drugs; and (iv) adequate renal, hepatic, and bone marrow function. The Drug-PIN^® system analyzes interactions between active and/or pro-drug forms by integrating biochemical, demographic, and genomic data from 110 SNPs. We selected DDI, DrugPin1, and DrugPin2 scores, resulting from concomitant medication interactions, concomitant medications, and SNP profiles, and DrugPin1 added to chemotherapy drugs, respectively. Thirty-four patients, taking a median of seven concomitant medications, were included. The median DrugPin1 and DrugPin2 scores were 42.6 and 77.7, respectively. In 13 patients, the DrugPin2 score was two-fold higher than the DrugPin1 score, with 7 (54%) of these patients experiencing severe toxicity that required hospitalization. On chi-squared testing for any toxicity, a doubled DrugPin2 score (p = 0.001) was significantly related to G3–G4 toxicity. Drug-PIN^® software may prevent severe adverse events, decrease hospitalizations, and improve survival in cancer patients.

In recent years, the first-line available therapeutic options for metastatic renal cell carcinoma (mRCC) have radically changed with the introduction into clinical practice of new immune checkpoint inhibitor (ICI)-based combinations. Many efforts are focusing on identifying novel prognostic and predictive markers in this setting. The complement system (CS) plays a central role in promoting the growth and progression of mRCC. In particular, mRCC has been defined as an “aggressive complement tumor”, which encompasses a group of malignancies with poor prognosie and highly expressed complement components. Several preclinical and retrospective studies have demonstrated the negative prognostic role of the complement in mRCC; however, there is little evidence on its possible role as a predictor of the response to ICIs. The purpose of this review is to explore more deeply the physio-pathological role of the complement in the development of RCC and its possible future use in clinical practice as a prognostic and predictive factor.

Tumors with an impaired ability to repair DNA double-strand breaks by homologous recombination, including those with alterations in breast cancer 1 and 2 (BRCA1 and BRCA2) genes, are very sensitive to blocking DNA single-strand repair by inhibition of the poly (ADP-ribose) polymerase (PARP) enzyme. This provides the basis for a synthetic deadly strategy in the treatment of different types of cancer, such as prostate cancer (PCa). The phase 3 PROfound study was the first to lead to olaparib approval in patients with metastatic castration resistant PCa (mCRPC) and BRCA genes mutations. In recent years, the benefit of combination therapy consisted of a PARP inhibitor (PARPi) plus an androgen receptor signalling inhibitor (ARSi), was evaluated as first-line treatment of mCRPC, regardless of the mutational state of genes, participating in the homologous recombination repair (HRR). This review explores the role of PARPi in PCa and analyses the data of latest clinical trials exploring the PARPi—ARSi combinations, and how these results could change our clinical practice.

Background: upper tract urothelial carcinoma (UTUC) is a rare and aggressive malignancy, which differs biologically and clinically from bladder cancer (BC). While immunotherapy has deeply changed the treatment landscape of BC, its role in UTUC remains uncertain. We conducted a systematic review and meta-analysis of randomized trials to investigate the efficacy of immune checkpoint inhibitors (ICIs) in UTUC.Methods: We searched MEDLINE/PubMed, the Cochrane Library, ASCO and ESMO libraries up to March 2026, including randomized phase II and III trials evaluating ICIs in UTUC. Overall survival (OS) was the primary endpoint. Secondary endpoints were progression-free survival (PFS), disease-free survival (DFS) and subgroup analyses in PD-L1-positive tumors. Summary hazard ratios (HRs) were calculated using fixed- or random-effects models, depending on heterogeneity.Results: Eleven randomized clinical trials were analyzed, comprising 2012 patients with UTUC (1009 treated with ICIs and 1003 controls). Immunotherapy showed an OS advantage compared to control (HR=0.78; 95% CI 0.63–0.95; p=0.02). In the metastatic setting, ICIs significantly improved OS (HR=0.73; 95% CI 0.64–0.84; p<0.0001), also confirmed with single-agent use, while no differences were reported based on PD-L1 expression. In the adjuvant setting, immunotherapy did not significantly improve OS (HR=1.43; 95% CI 0.60–3.39; p=0.42).Conclusions: Immunotherapy showed significant OS benefit in metastatic UTUC, supporting its use irrespective of PD-L1 expression. No clear advantage of adjuvant immunotherapy was demonstrated. Further studies are warranted to define the optimal use of ICIs in earlier disease stages in UTUC patients and to tailor the best treatment based on molecular tumor profile.