Abstract 27P
Background
Unlike other types of cancer that are sensitive to single-target agents, such as lung cancer and chronic myeloid leukemia, colorectal cancer (CRC) involves a complex network of interactions between activating oncogenes and is thus more likely to respond to multi-target therapy. Approximately 10% of CRC mutations are within the BRAF gene, the most frequent being BRAFV600E. While this mutation can be targeted with relatively high efficacy by single-target therapies, there exists a cohort of atypical BRAF mutations that confer higher resistance to currently available treatments. Furthermore, a large proportion of these atypical BRAF mutations are poorly understood.
Methods
We used principal component analysis and semi-supervised clustering learning methods to classify mutants unassigned by the previous BRAF classification system. By leveraging previously established protein-protein networks, we overlaid them with gene essentiality data to successfully classify 84 new BRAF mutations. We then evaluated the oncogenic potential of the newly classified atypical class-2 or -3 BRAF mutations compared to wild-type and class-1 BRAF mutations to validate that our extended system was consistent with the previously established BRAF classes. We also performed a network analysis to determine which genes were co-mutated for each BRAF class.
Results
Cell viability analysis of the BRAF-mutant Ba/F3 cells yielded no significant differences in the median AUC values between the new and old classification systems. Several key genes (including PIK3CA, EGFR, and MEK) were identified as potential drug targets (IC 50: 0.1 μM) for cell lines with class-2 and -3 atypical BRAF mutations. We found that atypical BRAF mutations have significantly more positive CERES scores than class-1 mutations and thus need to partner with other oncogenes to drive oncogenesis due to their lower oncogenic potential.
Conclusions
In conclusion, we extended the previous Yao classification system to establish a more comprehensive BRAF-mutant classification system, Yao Classification System Plus, that encompasses more atypical BRAF mutations. This allows for greater therapeutic options to target cells carrying these previously uncharacterized mutations.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
University of Texas MD Anderson Cancer Center.
Funding
National Cancer Institute , the Cancer Center Support Grant, and the Cancer Prevention & Research Institute of Texas.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
14P - Peripheral immune kinetics in survival prediction of small cell lung cancer patients treated with immune checkpoint blockade therapy
Presenter: MIGUEL GALINDO CAMPOS
Session: Poster session 09
15P - CBL E3 ubiquitin ligases are key inhibitory regulators in PD-1/LAG-3 co-signaling in human cancers, targeted through bispecific co-blockade
Presenter: Luisa Chocarro
Session: Poster session 09
16P - Terminally exhausted CD8+ T cells and increased immunosuppressive soluble factors in malignant ascites of patients with gastric cancer with peritoneal metastasis
Presenter: Hye Sook Han
Session: Poster session 09
17P - Continued expansion of long-lived effect CD8+ T cells associates with durable response post-PD-1 blockade
Presenter: Robert Watson
Session: Poster session 09
18P - Exposure of calreticulin is required for vitamin C immunomediated cancer surveillance
Presenter: Alessandro Cavaliere
Session: Poster session 09
19P - Preclinical and clinical significance of VEGF deprivation in ovarian cancer through a specific active immunotherapy
Presenter: Yanelys Morera
Session: Poster session 09
20P - The essential role of DNA repair in the pharmacological activities of AST-3424
Presenter: Fanying Meng
Session: Poster session 09
21P - Implications of KMT2C knockdown for DNA damage repair in breast cancer
Presenter: Philip Bredin
Session: Poster session 09
22P - Clinical significance of DNA damage response mutations in early stage NSCLC
Presenter: Haoran Zhang
Session: Poster session 09
23P - PMC-309: A highly selective anti-VISTA antibody reverses immunosuppressive TME to immune-supportive
Presenter: Cheon Ho Park
Session: Poster session 09