RBM10 mutation as a potential negative prognostic/predictive biomarker to therapy in non-small-cell lung cancer.
Authors: Reyes Amanda , Afkhami Michelle , Muddasani Ramya , Li Xiaochen , Massarelli Erminia , Salgia Ravi 
Published: July 2024

e20544

Background: According to WHO, lung cancer is the leading cause of cancer-related death worldwide, but treatment has advanced in the last decade. The widespread use of Next Generation Sequencing has led to the discovery of several pathogenic mutations including RNA binding motif 10 [RBM10], a part of the spliceosome complex that regulates splicing of pre-mRNA [Pan Q, Nat Genet. 2008]. The knock down of RBM10 increases the growth of mouse tumor xenografts [Hernández J, RNA Biol. 2016]. Mutated RBM10increased spliceosome inhibition in EGFR mutated lung cancer cells thereby contributing to EGFR TKI resistance [Bao Y, Cancer Res. 2023]. Methods: Electronic medical records were utilized to create a database of patients [50 patients] seen from 2018-2023 with NSCLC and RBM10 mutations, with appropriate IRB approval. For sub-group analysis, we separated into groups by rapid progression vs stable disease defined as progression free survival earlier than respective clinical trials. Fisher’s exact tests were used to assess the association between mutation and clinical outcomes. Results: From analysis of treatment response, 71% [20 patients out of 28] of the patients with complete treatment data had rapid progression of disease. In our patient dataset, 20 out of the 50 RBM10 mutated patients had EGFR mutations while 18 had KRAS mutations. RBM10 mutations did not seem to correlate with alterations in MSI stability as all patients had MSI stable disease and there was no relationship between the tumor mutation burden and the clinical response in the RBM10 mutated patients (odds ratio (OR) = 1.33, 95% CI 0.24-7.35, p = 0.741). In comparing the mutated RBM10 population to wild type RBM10 population, controlled for driver mutations, median PFS was 6.7 (95% CI [4.5, 17.]) compared to 13.9 (95% CI [10.4, 24.2]). RBM10 mutations in EGFR mutated patients often developed later in the course of disease, commonly at progression leading to late EGFR TKI resistance. The most common non driver concurrent mutation with RBM10 was TP53, while the most common VUS were SPTA1 and ZFHX3. TP53 mutation had a higher representation in the RBM10 mutated rapid progression group, OR (odds ratio) 8.081, 95% CI [0.773, 431/717], P-value = 0. 00838). The ZFHX3 mutation had a higher representation in the RBM10 mutated stable disease group OR 0.0430, 95% CI [0.0007, 0.5506]. Conclusions: From this single institution investigation, RBM10 mutations were associated with aggressive disease with treatment progression faster than median durations of response. RBM10 mutations with concurrent ZFHX3 and EGFR mutations were associated with more stable disease, while concurrent KRAS and TP53 predicted even more aggressive disease. However, once the RBM10 mutation developed in the EGFR population, rapid progression was observed, indicating a mechanism of late resistance. More investigation is warranted into RBM10 to further certify its use as a biomarker.