ARAF Amplification in Small-Cell Lung Cancer-Transformed Tumors Following Resistance to Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors.

Simple Summary: Despite the heterogeneity of resistance mechanisms to tyrosine kinase inhibitor (TKI)-targeting Epidermal Growth Factor Receptor (EGFR)-activating mutations, many induce the activation of MAPK signaling in the presence of EGFR-TKIs. ARAF gene amplification is identified as one such mechanism that activates MAPK signaling by directly interacting with RAS, yet its clinicopathologic characteristics remain poorly understood. In this study, we characterized nine cases with ARAF amplification resistant to EGFR-TKIs. Overall, these ARAF-amplified resistant tumors retained their original founder EGFR mutation and lacked secondary alterations. Furthermore, ARAF amplification was predominantly observed in female patients with EGFR exon 19 deletion. We also identified two cases showing a histologic transformation from lung adenocarcinoma to small-cell lung cancer (SCLC). ARAF amplification potentially fosters conditions that promote tumor cell survival and neuroendocrine marker transcription under EGFR-TKIs. Background/Objectives: Although tyrosine kinase inhibitors (TKIs) targeting EGFR-activating mutations significantly improved the outcome of EGFR-mutant NSCLC, resistance inevitably emerges. Despite the heterogeneity of these resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. While ARAF gene amplification is identified as a resistance mechanism that activates MAPK signaling by directly interacting with RAS, little is known about its clinicopathologic characteristics. Methods: We conducted a single-center retrospective analysis of the presence of ARAF amplification in re-biopsied samples in patients with EGFR-mutant NSCLC resistant to EGFR-TKIs. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. ARAF amplification was determined using a gene copy number assay. RNA sequence analysis was performed in patients with ARAF amplification as well as presenting histologic transformations to small-cell lung carcinoma (SCLC). Results: ARAF amplification was identified in five of ninety-seven patients resistant to erlotinib or gefitinib, and four of forty-eight patients resistant to Osimertinib. ARAF amplification was dominantly observed in female patients with EGFR exon 19 deletion. All ARAF-amplified tumors retained their founder EGFR mutation and were absent of secondary mutations. Two cases were found where ARAF amplification correlated with a histological transformation to SCLC. Conclusions: ARAF amplification was identified in 5–8% of EGFR-TKI-resistant tumors. The possible roles of ARAF in SCLC transformation warrant further investigation. [ABSTRACT FROM AUTHOR]