Abstract 5063: Exploring the mutational landscape of KRAS and NRAS in tumors with non-V600 BRAF mutations

Abstract Background: BRAF, a key modulator of the Mitogen-Activated Protein Kinase (MAPK) pathway, is observed in 7% of all cancers. Therapeutic response to MAPK inhibition (MAPKi) often relies on molecular distinctions between members of varying classes: Class 1 (V600), Class 2 and 3 (non-V600) BRAF mutants. Preliminary data indicates that co-occurring RAS mutations in non-V600 BRAF mutant cancers are less responsive to MAPKi treatment. This emphasizes the need to investigate the characteristics of RAS co-mutations in non-V600 BRAF mutant tumors. Methods: Genomic data was obtained from a cohort of 183, 292 patients provided by the AACR GENIE database (v14. 1). Patient samples were clustered according to their BRAF mutation status and co-occurring K/NRAS mutations: WT BRAF (n=60, 845) vs. non-V600 BRAF (n=1009). Samples were grouped based on cancer type: melanoma (n=3841), colorectal (n=15, 434), and non-small cell lung cancer (n=14640) and were further categorized according to key biochemical features of RAS GTPase function and overall GTPase activity. Results: This dataset revealed a diverse array of allelic variants of K/NRAS between cancer types and their underlying BRAF mutation status (Table 1). Non-V600 BRAF mutant cancers showed an enrichment for KRAS mutations linked to amplified nucleotide exchange (37. 9% vs. 13. 4%; p0. 0001) and hydrolysis-impairing NRAS mutations (41. 9% vs. 23%; p0. 0001), compared to WT BRAF cancers. Rare allelic variants including KRAS L19F, KRAS A146T, and NRAS G60E were seen in Class 2/3 BRAF mutants. Conclusion: This data suggests that non-V600 BRAF mutant tumors are characterized by a unique distribution of RAS mutations. More research into the difference in downstream effectors of RAS mutants overrepresented in non-V600 BRAF mutant tumors could provide important insights into how these tumors develop and resist targeted therapies. Table 1. Classification of KRAS and NRAS mutations in WT BRAF vs. non-V600 BRAF mutant tumors GTPase Function Cancer Type All cancers NSCLC Colorectal Melanoma BRAF mutation WT non-V600 p-value WT non-V600 p-value WT non-V600 p-value WT non-V600 p-value KRASmutation class Impaired hydrolysis n=20731 (79. 8%) n=167 (51. 9%) 0. 0001 n=6068 (86. 1%) n=60 (56. 6%) 0. 0001 n=4799 (68. 2%) n=16 (29. 1%) 0. 0001 n=38 (48. 1%) n=13 (50. 0%) 0. 4047 Nucleotide Exchange n=3475 (13. 4%) n=122 (37. 9%) n=530 (7. 5%) n=36 (34. 0%) n=1842 (26. 2%) n=36 (65. 5%) n=30 (38. 0%) n=12 (46. 2%) Hybrid n=1765 (6. 8%) n=33 (10. 2%) n=446 (6. 3%) n=10 (9. 4%) n=395 (5. 6%) n=3 (5. 5%) n=11 (13. 9%) n=1 (3. 8%) NRAS mutation class Impaired hydrolysis n = 974 (23. 0%) n=78 (41. 9%) 0. 0001 n=29 (18. 7%) n=9 (39. 1%) 0. 0196 n=188 (32. 6%) n=17 (68. 0%) 0. 0001 n=86 (5. 5%) n=22 (27. 8%) 0. 0001 Nucleotide Exchange n=459 (10. 8%) n=22 (11. 8%) n=5 (3. 2%) n=2 (8. 7%) n=48 (8. 3%) n=4 (16. 0%) n=93 (5. 9%) n=10 (12. 7%) Hybrid n=2811 (66. 2%) n=86 (46. 2%) n=121 (78. 1%) n=12 (52. 2%) n=341 (59. 1%) n=4 (16. 0%) n=1385 (88. 6%) n=47 (59. 5%) GTPase Activity BRAF mutation WT non-V600 p-value WT non-V600 p-value WT non-V600 p-value WT non-V600 p-value KRASmutation class Intermediate activity n=14408 (55. 3%) n=142 (44. 4%) 0. 0001 n=5082 (72. 3%) n=54 (50. 5%) 0. 0001 n=3540 (49. 9%) n=17 (31. 5%) 0. 0089 n=46 (56. 8%) n=13 (50. 0%) 0. 6516 High activity n=11630 (44. 7%) n=178 (55. 6%) n=1947 (27. 7%) n=53 (49. 5%) n=3552 (50. 1%) n=37 (68. 5%) n=35 (43. 2%) n=13 (50. 0%) NRAS mutation class Intermediate activity n=1364 (32. 2%) n=101 (55. 8%) 0. 0001 n=36 (23. 4%) n=12 (54. 5%) 0. 0041 n=239 (41. 8%) n=20 (87. 0%) 0. 0001 n=190 (12. 3%) n=34 (43. 0%) 0. 0001 High activity n=2868 (67. 8%) n=80 (44. 2%) n=118 (76. 6%) n=10 (45. 5%) n=333 (58. 2%) n=3 (13. 0%) n=1357 (87. 7%) n=45 (57. 0%) Citation Format: Chantel L. Mukonoweshuro, Emmanuelle Rousselle, April A. Rose. Exploring the mutational landscape of KRAS and NRAS in tumors with non-V600 BRAF mutations abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5063.