RBM10 mutation

Our results showed that RBM10C761Y-modulated ASPM203 promoted CCA progression in a Wnt/β-catenin signaling-dependent manner. This study may enhance the understanding of the regulatory mechanisms that link mutation-altering splicing variants to CCA.

In first-generation EGFR-TKIs treatment, gefitinib showed favorable efficacy compared to icotinib and erlotinib, particularly in patients with EGFR L858R mutations...In third-line treatments, the combination of osimertinib and anlotinib demonstrated superior efficacy compared to other regimens. Glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) mutation was an independent risk indicator of shorter OS following third-line treatments. Comprehending the tumor evolution in NSCLC is advantageous for assessing the efficacy and prognosis at each stage of treatment, providing valuable insights to guide personalized treatment decisions for patients.

Our study depicts the genomic characteristics and immune landscape, providing insights into the pathogenesis and possible therapeutic guidance of super MPLC.

Additionally, HIST1H2BD represents a novel resistance mutation to osimertinib. All of these findings offer valuable insights for making personalized treatment strategies for NSCLC patients.

Cancer-derived mutant RBM10-I316F fails to bind to uL18 and uL5 and to inactivate c-Myc, thus incapable of suppressing tumorigenesis. Our findings uncover RBM10 as a pivotal c-Myc repressor by cooperating with uL18 and uL5 in lung cancer cells, as its failure to do so upon mutation favors tumorigenesis.

RBM10 can inhibit the proliferation and invasion of lung adenocarcinoma cells through negative regulation and promote the apoptosis of lung adenocarcinoma cells through immunomodulatory mechanisms. The expression level of RBM10 affects the efficacy of targeted drug therapy and the survival prognosis of lung adenocarcinoma patients, which has a certain guiding significance for the clinical treatment of these patients.

Combined treatment with spliceosome inhibitor improved the therapeutic efficacy of EGFR tyrosine kinase inhibitor osimertinib and overcame drug resistance, especially in RBM10-deficient LUAD. Combined treatment with spliceosome inhibitor improved the therapeutic efficacy of EGFR tyrosine kinase inhibitor osimertinib and overcame drug resistance, especially in RBM10-deficient LUAD. Together, this study establishes RBM10 as a tumor suppressor akin to p53 and provides a therapeutic strategy of targeting the splicing machinery in EGFR-driven LUAD.

L858R have distinct co-mutations and copy number alterations compared to ex19del, in addition to a higher representation of smoking mutational signature and TRU subtype. TP53 co-mutations are more frequently observed in higher stage tumours and are associated with WGD. Our findings highlight the molecular heterogeneity of resected EGFR-mutated NSCLC, which could contribute to the differential outcomes to adjuvant osimertinib between ex19del and L858R.

Neoadjuvant osimertinib in surgically resectable EGFR-mutated NSCLC achieved a 15% mPR, which did not meet the primary endpoint. Treatment was safe and may induce pathological responses and lymph node-downstaging of disease. Co-mutations in RBM10 may limit response.

Three hundred and twenty-nine non-synonymous somatic variants were identified in 161 genes among these 35 patients. EGFR, TP53, LRP1B, RBM10, KRAS, NTRK3, RB1, ALK, APC, FAT2, KEAP1, MED12 and MLL3 were described as frequently mutated genes with prevalence more than 10%. Patients harboring KRAS mutation had more relapse in 1 year after surgical resection. For the expression of these frequently mutated genes in 149 stage I patients, multivariate Cox regression analyses showed that the expression of RBM10 was positively associated with RFS in all patients (HR 0.40, 95% CI 0.15-1.0, p = 0.052), and the expression of APC was negative associated with RFS in patients with EGFR mutations (HR 3.10, 95% CI 1.54-6.26, p = 0.002). Stage I LUAD patients with KRAS mutation or low RBM10 expression are inclined to receive more positive intervention rather than just disease surveillance.

CONCLUSION RBM10 mutations in NSCLC are strongly associated with actionable driver mutations. Targeting RNA splicing alone or in combination with specific on-target inhibition may improve therapeutic efficacy of current targeted and immunotherapy therapy of NSCLC.

We compared the mutation landscape of MP-LUAD and SP-LUAD and identified six differentially mutated genes (RBM10, CDK4, ATRX, NTRK1, PREX2, SS18), and certain SNV loci in TP53 and EGFR which might play key roles in lineage decomposition in multifocal samples. These findings may provide insight into personalized prognosis prediction and new therapies for MP-LUAD patients.

This study provided evidence for unravelling the previously unknown genomic underpinnings associated with SSN-LUAD evolution from pGGN to HGGN to PSN, proving that HGGN was an intermediate SSN form between pGGN and PSN genetically.

Co-inhibition of Bcl-xL and mutant EGFR overcame resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations, and on the impact of splicing factor deficiency in the modulation of sensitivity to targeted kinase inhibitor cancer therapy.

This study performed the first direct comparative genomic profiling in pathologic stage I invasive LUAD by radiological subtype, highlighting a less complex genomic architecture of SSNs, which might be the molecular interpretation of their indolent tumor behavior.

Furthermore, a higher level of TMB was found in aged group compared with young group. In this study, we revealed the differences of somatic genetic mutations and TMB between young and aged LUAD patients, which may provide directions of targeted therapy and advantages of immunotherapy for the elderly in the future.

Finally, RBM10 re-expression in RBM10 null cells reversed metastatic competency in vivo. In conclusion, RBM10 loss alters the ratio of cassette exon inclusion events in a subset of transcripts that regulate interactions between the ECM and the cytoskeleton, leading to RHO/RAC activation and governing a process favoring increased cell movement and metastatic competence.

Most patients with splicing factor mutant NSCLCs are smokers whose cancers commonly harbor RBM10 mutations and higher TMB compared to other driver-positive cancers. The characterization of this profile is key to identifying appropriate patients for ongoing targeted therapy trials for this population.

Efficacy studies in patient-derived xenograft (PDX) models, as well as genomic profiling of spliceosome-mutant cellular models in response to PRT543 are ongoing. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831).