Abstract 264: Framework to determine fusion junction of novel RNA fusions and their actionability for personalized therapy of lung cancer patients
Authors: Verma Prisha , Rankothgedera Sakuni , Castillo Micah , Gunaratne Preethi 
Published: April 2023

Background: Current therapies including chemotherapy, radiotherapy, and targeted therapies have not worked well for treating lung cancer as is evident by the high lung cancer-related mortality rate. This is because we continue to treat all lung cancers as a homogenous disease. Therefore, personalized therapies based on individual molecular characteristics of patient tumors are needed to improve lung cancer treatment outcomes.

Objective: The objective of the current project is to identify novel actionable RNA fusions that can be targeted for the personalized treatment of lung cancer. Fusions, including the ones that are created by joining at the RNA level, can form during cancer development and thus present an attractive way of personalized cancer treatment.

Methodology: A list of RNA fusion candidates was processed through a multistep pipeline framework to map the fusion junction of these novel fusions and evaluate their actionability. We had previously obtained this list of RNA fusions by mining the RNA sequencing data from lung cancer samples. The workflow of the project included the following steps: 1) a literature search to assess the oncogenic role of individual gene partners, 2) Blat to map the fusion junction 3) cBioPortal/Survival analysis to predict the association of individual gene partners with lung cancer patient survival and prognosis, 4) cBioPortal/Co-Expression analysis to study if the gene partners are expressed together or have common gene partners and lastly, 5) Open Reading Frame (ORF) Finder to identify if the fusion is predicted to be translated and makes a unique product.

Results: RNA fusions such as TMPRSS13-TMPRSS13, SUPT6H-ESR1, PTPRK-RSPO3, and KIF5B-RET were investigated and fusion junctions were successfully determined. Gene partners from multiple fusion pairs (e.g., SUPT6H-ESR1 and KIF5B-RET) were found to have an oncogenic role in lung cancer. Mutations in KIF5B and RET genes were found to associate with poor survival in the TCGA dataset suggesting that the novel RNA fusions may also play an oncogenic role in lung cancer. Lastly, several of these RNA fusions generated unique ORFs suggesting that these fusions are predicted to be translated and these novel proteins can be selectively targeted sparing the normal cells that don’t harbor these mutants.

Future directions: Next steps will involve preclinical testing of the driver role of these novel RNA fusions and testing of existing drugs such as RET inhibitors for their efficacy to treat lung cancer in tumors that harbor these novel RNA fusions.

Citation Format: Prisha Verma, Sakuni Rankothgedera, Micah Castillo, Preethi Gunaratne. Framework to determine fusion junction of novel RNA fusions and their actionability for personalized therapy of lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 264.