Abstract 493: Genomic landscape of targetable drivers in lung cancer.

Abstract Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death worldwide. As global smoking rates decline, the incidence of lung cancer in never-smokers (LCINS) is rising, motivating more detailed investigation into its etiology. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers and is often driven by alterations in the MAPK pathway, including receptor tyrosine kinases (RTKs) and downstream RAS-RAF-MEK signaling, which are key targets of many current molecular therapies. However, 12-30% of NSCLC lack actionable driver alterations, and rare drivers (≤5%) remain poorly characterized, leaving many patients without targeted options. Currently, no large-scale study has systematically compared the distribution of genomic drivers by smoking history and ancestry, or comprehensively profiled rare oncogenic drivers in NSCLC. We analyzed whole-genome and RNA sequencing data from 799 treatment-naïve NSCLC from never-smokers (NS-NSCLC) and 336 NSCLC from smokers (S-NSCLC) in the Sherlock-Lung study. We integrated single-nucleotide variants (SNVs), structural variants, copy number alterations, and RNA-seq data with public cancer databases to identify canonical and potential drivers. Overall, 98% of NSCLC harbored at least one genomic driver. More than half of both smokers and never-smokers carried at least one RTK/RAS/RAF (RPA)-positive driver. NS-NSCLC more frequently carried RPA-positive drivers than S-NSCLC (p = 3.16 × 10-19) and showed higher frequencies of fusions and tumor-suppressor deletions (p 7.10 × 10-3). In contrast, S-NSCLC showed higher frequencies of KRAS mutations, oncogene amplifications, and rare drivers (p 2.10 × 10-4). RPA-negative tumors were enriched in PI3K, NOTCH, and WNT signaling pathways, suggesting alternative oncogenic pathways may drive some NSCLC. We describe 60 novel rare driver genes in RPA-negative NSCLC. Among NS-NSCLC, tumors from East Asians (EAS) showed significantly higher EGFR mutations (p = 1.27 × 10-13), while tumors from Europeans (EUR) exhibited heterogeneous SNV and fusion drivers. EGFR mutations from EAS tumors were enriched for classical activating variants, while EUR tumors had greater EGFR mutation heterogeneity. Furthermore, within RPA-positive NSCLC, EUR tumors showed a broader spectrum of RPA alterations, including ERBB3, FGFR3/4, and ARAF, whereas EAS tumors predominantly harbored canonical RTK/MAPK pathway oncogene mutations. Together, these multi-omics analyses describe the genomic driver landscape of NSCLC in smokers and never-smokers, including rare molecular subtypes previously undetected in genomic landscapes. This study may help guide future molecular testing strategies and therapeutic management, particularly for patients with rare or currently non-targetable molecular alterations. Citation Format: Olivia Lee, Soo-Ryum Yang, Wei Zhao, Huu Phuc Hoang, Tongwu Zhang, Maria Teresa Landi. Genomic landscape of targetable drivers in lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 493.