Journal of Experimental & Clinical Cancer Research最新文献

Background: The KRAS^G12C mutation is one of the special mutation types in patients with colorectal cancer liver metastasis (CRLM). Although several small molecule inhibitors specifically targeting KRAS^G12C mutation have been developed, they have only shown limited clinical benefits for CRLM patients. Thus, alternative approaches are still needed.

Methods: We screened out the differentially expressed gene Aldo-keto reductase family 1 member B10 (AKR1B10) between the KRAS^G12C mutation and wild-type CRLM through RNA sequencing, and characterized the tumor microenvironment (TME) changes of the KRAS^G12C mutation CRLM using multi-omics analysis. The role of AKR1B10 in the TME and its progression of KRAS^G12C mutation CRLM was confirmed by in vitro and in vivo experiments, and the molecular mechanism of lactate on neutrophils reprogramming was detected by immunofluorescence, western blot and Chip-qPCR.

Results: AKR1B10 was highly expressed in the KRAS^G12C mutation CRLM and was associated with a poor prognosis. Mechanistically, AKR1B10 promotes the recruitment of neutrophils in the TME by CXCL8/CXCR2 pathway. Meanwhile, AKR1B10 could promote the production of lactate by regulating crucial glycolytic enzymes. The increased lactate accumulation in the TME promoted histone lactylation of neutrophils, which induced PD-L1 transcription and prompted the reprogramming of neutrophils to an immunosuppressive phenotype.

Conclusion: AKR1B10 facilitated immune evasion of KRAS^G12C mutation CRLM by recruiting and reprogramming neutrophils to remodel the immunosuppressive TME, providing a potential therapeutic target for KRAS^G12C mutation CRLM patients.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapeutic options, where platinum-based chemotherapy such as carboplatin serves as a cornerstone of treatment. Despite initial responses, the rapid emergence of acquired resistance remains a major clinical barrier. Understanding the molecular adaptations that drive platinum resistance is essential to develop strategies to restore sensitivity and identify alternative vulnerabilities.

Methods: We generated four isogenic patient-derived xenograft (PDX) pairs (WHIM30, BCM‑2147, BCM‑3887, BCM‑7482) through serial carboplatin exposure to model acquired resistance in TNBC. Bulk RNA sequencing, immunohistochemistry, and histopathological analyses were performed to define transcriptomic and phenotypic changes associated with resistance. Synergistic therapeutic combinations were identified using high-throughput drug screening in carboplatin-resistant (CR) PDX-derived models, followed by in vivo validation in NSG mice. Tumor growth and survival were assessed using mixed-effects modeling, two-way ANOVA, and Welch's student t-test.

Results: The resulting isogenic PDX pairs captured both convergent and model-specific adaptations to carboplatin. CR tumors demonstrated heterogeneous activation of DNA damage repair pathways, including restoration of BRCA1-dependent homologous recombination (BCM‑2147, WHIM30) and compensatory upregulation of mismatch repair (BCM‑3887). In the BRCA1-mutant BCM‑7482 model, resistance correlated with HORMAD1 upregulation, suggesting an alternative HRD-associated mechanism. Morphologically, BCM‑7482CR tumors exhibited a significant increase in nuclear size compared to their sensitive counterpart (p < 0.0001). Drug screening identified mTOR pathway inhibition as a recurrent vulnerability across CR models. Sacituzumab govitecan (SG) combined with Everolimus produced robust synergy in vitro and superior tumor control in vivo compared to single agents in both WHIM30CR and BCM‑2147CR. A second combination, Everolimus + Selinexor (KPT‑330), also reduced tumor burden, achieving statistical significance in an expanded WHIM30CR cohort and suppressing metastatic progression in the intrinsically resistant WHIM2 model.

Conclusions: Isogenic PDX models of TNBC provide a powerful platform to define molecular mechanisms of acquired carboplatin resistance and uncover actionable therapeutic strategies. Our findings reveal multiple adaptive routes to platinum resistance, including restoration of homologous recombination and activation of alternative DNA repair programs. Synergistic interactions between SG and mTOR inhibition offer a promising avenue for overcoming resistance, supporting further clinical investigation of these combinations in TNBC.

Background: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the uncontrolled growth of immature myeloid cells, often with a poor prognosis due to therapy resistance. This study investigated the prognostic significance of SRSF2 mutations in AML and their impact on chemotherapeutic drug sensitivity.

Methods: The prognostic value of SRSF2 mutations was analyzed in AML patients. SRSF2-mutant cell models were generated via lentiviral transduction for drug sensitivity testing. Xenograft mice were used to assess daunorubicin (DNR) efficacy. Mechanistic studies included transcriptomics, splicing analysis, mRNA stability, polysome profiling, RNA immunoprecipitation, and metabolic assays to identify targetable resistance pathways.

Results: Clinical analysis revealed that SRSF2 mutations decreased the survival of AML patients. In vitro experiments demonstrated that SRSF2 mutation reduced the sensitivity of AML cells to drugs such as DNR and homoharringtonine but did not affect the response to venetoclax. In mouse models, DNR treatment was effective against wild-type AML but showed significantly reduced efficacy in suppressing tumors and improving survival in SRSF2-mutant AML. Mechanistically, SRSF2 mutation impaired the interaction between the SRSF2 protein and THBS1 mRNA, prolonging the THBS1 mRNA half-life and enhancing its translation efficiency, leading to THBS1 protein accumulation. Additionally, the mutation altered the splicing pattern of ETV7 and upregulated its expression, potentially mediating DNR resistance. Metabolic analysis revealed that mutant cells presented increased spare respiratory capacity, supporting energy demands under stress. Inhibition of the PDGFB pathway (CP-673451) synergistically enhanced the cytotoxic effect of DNR on mutant cells.

Conclusions: SRSF2 mutations promoted DNR resistance through multiple mechanisms, and targeted combination therapy with PDGFB pathway inhibitors may represent a novel strategy to improve therapeutic outcomes in patients with mutations.