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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Mechanism exploration and model construction for small cell transformation in EGFR-mutant lung adenocarcinomas
Yan Li1, Tongji Xie2,3, Shouzheng Wang2,4
1State Key Laboratory of Molecular Oncology, Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Abstract:
Small-cell lung cancer (SCLC) transformation accounts for 3-14% of resistance in EGFR-TKI relapsed lung adenocarcinomas (LUADs), with unknown molecular mechanisms and optimal treatment strategies. We performed transcriptomic analyses (including bulk and spatial transcriptomics) and multiplex immunofluorescence on pre-treated samples from LUADs without transformation after EGFR-TKI treatment (LUAD-NT), primary SCLCs (SCLC-P) and LUADs with transformation after EGFR-TKI treatment (before transformation: LUAD-BT; after transformation: SCLC-AT). Our study found that LUAD-BT exhibited potential transcriptomic characteristics for transformation compared with LUAD-NT. We identified several pathways that shifted during transformation, and the transformation might be promoted by epigenetic alterations (such as HDAC10, HDAC1, DNMT3A) within the tumor cells instead of within the tumor microenvironment. For druggable pathways, transformed-SCLC were proved to be less dependent on EGF signaling but more relied on FGF signaling, while VEGF-VEGFR pathway remained active, indicating potential treatments after transformation. We also found transformed-SCLC showed an immuno-exhausted status which was associated with the duration of EGFR-TKI before transformation. Besides, SCLC-AT exhibited distinct molecular subtypes from SCLC-P. Moreover, we constructed an ideal 4-marker model based on transcriptomic and IHC data to predict SCLC transformation, which obtained a sensitivity of 100% and 87.5%, a specificity of 95.7% and 100% in the training and test cohorts, respectively. We provided insights into the molecular mechanisms of SCLC transformation and the differences between SCLC-AT and SCLC-P, which might shed light on prevention strategies and subsequent therapeutic strategies for SCLC transformation in the future.
Insights
Small-cell lung cancer (SCLC) transformation in EGFR-TKI resistant lung adenocarcinoma (LUAD) is driven by epigenetic changes, not the microenvironment. Transformed SCLC shifts to FGF signaling, showing immune exhaustion and distinct subtypes, aiding future treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Small-cell lung cancer (SCLC) transformation is a key mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma (LUAD), occurring in 3-14% of relapsed cases.
- The molecular underpinnings and optimal therapeutic approaches for SCLC transformation remain largely undefined, necessitating further investigation.
Purpose of the Study:
- To elucidate the molecular mechanisms driving SCLC transformation in EGFR-TKI relapsed LUAD.
- To identify potential therapeutic targets and predictive biomarkers for SCLC transformation.
- To differentiate the molecular subtypes of SCLC post-transformation (SCLC-AT) from primary SCLC (SCLC-P).
Main Methods:
- Transcriptomic analyses, including bulk and spatial transcriptomics, were performed on patient samples.
- Multiplex immunofluorescence was utilized to analyze protein expression.
- Samples included LUAD without transformation (LUAD-NT), primary SCLC (SCLC-P), and LUAD with transformation (LUAD-BT and SCLC-AT).
Main Results:
- LUAD-BT displayed transcriptomic features indicative of transformation compared to LUAD-NT.
- Epigenetic alterations within tumor cells (e.g., HDAC10, HDAC1, DNMT3A) were identified as potential drivers of transformation.
- Transformed SCLC showed reduced dependence on EGF signaling, increased reliance on FGF signaling, and sustained VEGF-VEGFR pathway activity.
- Transformed SCLC exhibited an immuno-exhausted phenotype, correlated with EGFR-TKI treatment duration.
- SCLC-AT demonstrated distinct molecular subtypes compared to SCLC-P.
- A 4-marker model accurately predicted SCLC transformation with high sensitivity and specificity.
Conclusions:
- SCLC transformation in EGFR-TKI relapsed LUAD is driven by intrinsic epigenetic alterations.
- Targeting FGF and VEGF-VEGFR pathways may offer therapeutic benefits post-transformation.
- The immuno-exhausted status and distinct subtypes of transformed SCLC provide avenues for immunotherapy development.
- A predictive model for SCLC transformation can guide clinical management and therapeutic strategies.
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