EDITORIAL: INNOVATIVE DRUG COMBINATIONS FOR ENHANCED SOLID TUMOR TREATMENT EFFICACY

Giovanna DamiaMassimo Broggini^*

• Oncology, Mario Negri Institute for Pharmacological Research (IRCCS), Milano, Italy

In the same setting (NSCLC), Jin et al. (https://doi.org/10.3389/fonc.2025.1533059) used a tri-specific antibody targeting EGFR, cMET and VEGF. The rationale behind the use of this tri-specific antibody is based on the known crosstalk between the three targeted signaling pathways. This strategy was superior to the use of single EGFR or bispecific EGFR/cMET antibodies. Furthermore, the authors showed that the strong efficacy of the trsipecific antibody could be even enhanced when combined with chemo or radiotherapy in xenografts models with strong and durable tumor regression without Two case reports, one in a patient with rare cervical sarcomatoid carcinoma (https://doi.org/10.3389/fonc.2025.1586531) and the other in Grade 2 meningioma (https://doi.org/10.3389/fonc.2025.1587752), highlighted the use of immunotherapy. In the first report, the authors used a combination of permbrolizumab (anti PD-1) with bevacizumab (targeting angiogenesis) that resulted in a prolonged PFS and OS. Interestingly, the combination was rationally designed based on the molecular characteristics of the patient, again supporting the notion that targeted combinations has stronger potential over empirical ones. The second case report indeed used immunotherapy as single therapy, based on the molecular characteristics of the tumor patient bearing a mutation in PBMR1 (a gene involved in control of genomic stability) that, when mutated, in renal carcinoma associates with response to immune-checkpoint inhibitors.Combinations of targeted therapy and chemotherapy have been tested in two case reports using as targeted agent anlotinib, a drug hitting several tyrosine kinases including VEGFR, FGFR, PDGFR and c-kit. In the first report (https://doi.org/10.3389/fonc. 2025 Interestingly, the patient was initially treated with chemotherapy alone, that resulted in a slow progression. Addition of anlotinib in subsequent treatments not only caused a significant tumor reduction, but also ameliorated the general symptoms of the patients.Another important rational design for combinations includes the use of drugs targeting DNA repair.An interesting report (https://doi.org/10.3389/fonc.2025.1626301) showed that the addition of the thymidine analogue CldU was able to significantly enhance the response of BRCA2-mutated cells to olaparib (a PARP inhibitor). What is even more important, is that the use of CldU was able to overcome resistance to PARP inhibitors. This is particularly important because the efficacy of PARP inhibitors in clinic is hampered by the onset of drug resistance.The review by Zhou et a.l (https://doi.org/10.3389/fonc.2025.1582738) was centered on SLFN11 as a potential biomarker of sensitivity to DNA targeting agents. The authors gave an overview of the functions of SLFN11 but, in the context of the Research Topic, they proposed treatment strategies based on the expression status of SLFN11. This represents an additional way to foster combinations, as already discussed, based on the molecular characteristics of the tumors, and further prove that rational combination could even rise to synthetic lethality sparing normal cells.Interestingly, in the manuscript by Chen X. et al. (https://doi.org/10.3389/fonc.2025.1641979) a screening of an in-house panel of small molecules against hepatocellular carcinoma (HCC) cancer stem cells led to the identification of a new compound C504244, able to interfere with the  -catenin signaling. Lenvatinib, a multi-targeted TKI, is approved for first-line treatments for advanced HCC.As resistance to lenvatinib has been associated to overactivation of -catetin and that cancer stem cell have been implicated in therapy resistance in HHC, the authors combined C504244 and lenvatinib both in vitro and in vivo models and found how this combination reverted lenvatinib resistance.A triple combination (palbociclib, a CDK4/6 inhibitor, PF-07104091, a CDK2 inhibitor and SX-682, a dual CXCR1 and CXCR2-CXCR1/2-) was tested as potential new effective treatment in preclinical models of melanoma (https://doi.org/10.3389/fonc.2025.1609735). The triple treatment was able not only to reduce melanoma tumor cell viability, to interfere with tumor growth more effectively in BRAF WT NRAS WT melanoma cells, but also induced a less immunosuppressive tumor immune microenvironment opening up the road for the design of clinical trials for immunochekpointresistant melanomas without BRAF mutation.Finally, in the last manuscript (https://doi.org/10.3389/fonc.2025.1590497), trastuzumab combined with low-dose nab-paclitaxel and radiotherapy was able to induce a very good disease control in a 86-years old man with a HER2-positive salivary duct carcinoma (SDC), a rare and aggressive malignancy. This case highlights the efficacy and safety of HER2-targeted combination therapy in elderly SDC patients, offering valuable insights into biomarker-driven personalized treatment strategies for this population.All the manuscripts presented in this Research Topic support how rational, biology-guided combination strategies represent one of the most promising avenues to improve outcomes in solid tumors. Continued efforts to optimize and validate integrated therapeutic approaches will be crucial to translate these advances into durable and meaningful clinical benefits for patient with solid tumors.