Comprehensive Analysis of ADC Target Expression in Invasive Lobular Carcinoma
Authors
Jason Mouabbi¹, Vladimir Kushnarev², Daria Goncharova², Oleg Baranov², Konstantin Chernyshov², Sofia Kust², Nikita Kotlov², Patrick Clayton², Debu Tripathy¹, Funda Meric-Berstam¹
- MD Anderson
- BostonGene Corp., Waltham, Massachusetts, USA
Abstract
Introduction:
Antibody-drug conjugates (ADCs) targeting specific surface antigens are critical for the advancement of targeted cancer therapies. Here, we analyzed RNA sequencing (RNA-seq) data from invasive lobular carcinoma (ILC) samples to identify novel cell surface protein candidates for designing new and highly specific ADCs, aiming to minimize side effects and improve patient outcomes.
Methods:
RNA-seq data from the BostonGene internal breast cancer (BC) cohort (non-ILC n=518, ILC n=138), TCGA-BRCA (non-ILC n=815, ILC n=233) cohort, and normal tissue samples in the Adult GTEx dataset (n=7862) for 82 cell surface protein genes were assessed together. BC samples were classified as histo-molecular ILC if they showed at least one of the following: ILC histology, CDH1 truncation, gene loss, Z-scores of < -1.5 for gene expression. Among the ILC samples, some were classified as classic (low-grade and Lum A or B; n=224) and non-classic ILC (high-grade, HER2-enriched, or Basal-like; n=28). We also classified all ILC samples as high- (HG-ILC, n=142) or low-grade (LG-ILC, n=229) based on molecular grading. Information on ADC targets and relevant clinical trials was extracted from ClinicalTrials.gov.
Results
Among the 82 cell surface protein genes assessed, 18 were included in our analysis because they were highly expressed (≥4 log2 transcripts per million (TPM)) in at least one subtype. These genes are: LYPD3*, FOSL2, CD276*, CRIM1*, PRLR*, PVRL4*, TPBG*, VTCN1*, ERBB3**, ALCAM, CD46, ERBB2**, SLC39A6**, ST14*, CD74, TACSTD2*, GPNMB, and MUC1*. Genes marked with * showed low expression in normal tissues (<2 log2 TPM), while genes marked with ** showed low expression in normal tissue and are being investigated in ≥5 clinical trials. Both non-ILC and ILC groups showed high expression of ERBB3**, ERBB2**, ALCAM, CD46, SLC39A6**, ST14*, CD74, TACSTD2*, GPNMB, and MUC1*. Among the ILC samples, LYPD3* was highly expressed only in non-classic ILC. FOSL2 and CD276* showed low expression in HG-ILC. CRIM1* showed high expression in unclassified ILC, LG-ILC, and classic ILC. PRLR* and PVRL4* had high expression in LG-ILC and classic ILC. TPBG* and VTCN1* were highly expressed in non-ILC, unclassified ILC, LG-ILC, and classic ILC, but showed low expression in HG-ILC and non-classic ILC. Interestingly, the low expression of several targets in normal tissues (marked * and **) indicate their suitability as ADC targets for treating ILC while minimizing adverse effects.
Conclusion:
We uncovered distinct ADC target expression landscapes between classic and non-classic ILCs, as well as between ILC and non-ILC samples. While both classic and non-classic ILCs showed high expression of several ADC targets, they differed notably in TPBG, CRIM1, PRLR, and VTCN1 expression. The low expression of several analyzed genes in normal tissues revealed their potential as targets for highly specific ADCs with reduced adverse effects. Our findings underscore the necessity for clinical trials to account for varied ADC target expression landscapes across ILC subtypes to optimize efficacy and safety of ADC-based treatments, subsequently improving patient outcomes.
Antibody-drug conjugates (ADCs) targeting specific surface antigens are critical for the advancement of targeted cancer therapies. Here, we analyzed RNA sequencing (RNA-seq) data from invasive lobular carcinoma (ILC) samples to identify novel cell surface protein candidates for designing new and highly specific ADCs, aiming to minimize side effects and improve patient outcomes.
Methods:
RNA-seq data from the BostonGene internal breast cancer (BC) cohort (non-ILC n=518, ILC n=138), TCGA-BRCA (non-ILC n=815, ILC n=233) cohort, and normal tissue samples in the Adult GTEx dataset (n=7862) for 82 cell surface protein genes were assessed together. BC samples were classified as histo-molecular ILC if they showed at least one of the following: ILC histology, CDH1 truncation, gene loss, Z-scores of < -1.5 for gene expression. Among the ILC samples, some were classified as classic (low-grade and Lum A or B; n=224) and non-classic ILC (high-grade, HER2-enriched, or Basal-like; n=28). We also classified all ILC samples as high- (HG-ILC, n=142) or low-grade (LG-ILC, n=229) based on molecular grading. Information on ADC targets and relevant clinical trials was extracted from ClinicalTrials.gov.
Results
Among the 82 cell surface protein genes assessed, 18 were included in our analysis because they were highly expressed (≥4 log2 transcripts per million (TPM)) in at least one subtype. These genes are: LYPD3*, FOSL2, CD276*, CRIM1*, PRLR*, PVRL4*, TPBG*, VTCN1*, ERBB3**, ALCAM, CD46, ERBB2**, SLC39A6**, ST14*, CD74, TACSTD2*, GPNMB, and MUC1*. Genes marked with * showed low expression in normal tissues (<2 log2 TPM), while genes marked with ** showed low expression in normal tissue and are being investigated in ≥5 clinical trials. Both non-ILC and ILC groups showed high expression of ERBB3**, ERBB2**, ALCAM, CD46, SLC39A6**, ST14*, CD74, TACSTD2*, GPNMB, and MUC1*. Among the ILC samples, LYPD3* was highly expressed only in non-classic ILC. FOSL2 and CD276* showed low expression in HG-ILC. CRIM1* showed high expression in unclassified ILC, LG-ILC, and classic ILC. PRLR* and PVRL4* had high expression in LG-ILC and classic ILC. TPBG* and VTCN1* were highly expressed in non-ILC, unclassified ILC, LG-ILC, and classic ILC, but showed low expression in HG-ILC and non-classic ILC. Interestingly, the low expression of several targets in normal tissues (marked * and **) indicate their suitability as ADC targets for treating ILC while minimizing adverse effects.
Conclusion:
We uncovered distinct ADC target expression landscapes between classic and non-classic ILCs, as well as between ILC and non-ILC samples. While both classic and non-classic ILCs showed high expression of several ADC targets, they differed notably in TPBG, CRIM1, PRLR, and VTCN1 expression. The low expression of several analyzed genes in normal tissues revealed their potential as targets for highly specific ADCs with reduced adverse effects. Our findings underscore the necessity for clinical trials to account for varied ADC target expression landscapes across ILC subtypes to optimize efficacy and safety of ADC-based treatments, subsequently improving patient outcomes.
Latest publications
