2024 Hot Topic in Basic & Translational Science: Tolerance & Resistance to Targeted Therapy in NSCLC - Posters-PP01.14: Paired Sample Analyses of NSCLC After SCLC Transformation

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The study focuses on the phenomenon of non-small cell lung cancer (NSCLC) transforming into small cell lung cancer (SCLC), a mechanism of drug resistance, particularly in EGFR-mutant cases. About 10% of EGFR-mutant NSCLC tumors reportedly undergo such a transformation. Loss of TP53 and RB1 genes increases the risk of this transformation; however, the specific genetic mechanisms remain elusive.<br /><br />Researchers conducted a paired sample analysis involving NSCLC and SCLC tumors from nine patients. They performed next-generation sequencing of DNA and RNA to assess molecular alterations and the expression of neuroendocrine (NE) markers, which could be potential targets for antibody-drug conjugates (ADCs). Paired tumor samples with transitions from NSCLC to SCLC were included in the study.<br /><br />The findings confirmed frequent alterations in TP53 and RB1 before and after SCLC transformation. In most cases, TP53 mutations persisted through the transformation, while some acquired TP53 mutations after transformation. RB1 mutations were also common, with some cases showing an acquisition of RB1 mutations post-transformation. Additionally, other mutations such as PIK3CA, PRKDC, and EP300 were gained post-transformation, while mutations like CDKN2A and KRAS were lost.<br /><br />Gene expression analysis revealed increased expression of several NE markers such as ASCL1, CHGA, NEUROD1, SEZ6, and SYP after transformation, suggesting their potential role in this transition. The results imply that lineage plasticity, involving these genetic and expression changes, might underpin the resistance mechanism leading to SCLC transformation. This study enhances understanding of genetic changes during transformation, potentially guiding future therapeutic strategies targeting transformed SCLC tumors. The research underscores the complexity of cancer evolution and the need for targeted approaches to effectively manage and treat transformations of NSCLC into SCLC.

Asset Subtitle

Brinda Gupta

Keywords

NSCLC

SCLC

EGFR-mutant

TP53

RB1

transformation

next-generation sequencing

neuroendocrine markers

lineage plasticity

cancer evolution