Abstract
Background: Large-scale genomic profiling has cataloged the prevalence of single base substitution (SBS) mutational signatures associated with the activity of Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) cytidine deaminases in breast cancer (BC). These mutational signatures are enriched in metastatic BC (mBC) compared to early tumors indicating an association with poor prognosis and a potential function in therapy resistance and disease progression. We sought out to investigate whether APOBEC3 mutational signatures can serve as biomarkers for poor treatment outcomes and if APOBEC3 mutagenesis-driven genomic instability can induce therapy resistance in mBC.
Methods: We analyzed SBS mutational signatures in 3,880 BC samples with paired tumor-normal sequencing by the MSK-IMPACT assay using the SigMA algorithm. We utilized the detailed clinical annotation to assess the clinical characteristics of APOBEC3-dominant tumors including survival analyses on endocrine and targeted therapies. We generated cellular models of BC to investigate the molecular drivers of APOBEC3 mutagenesis and its function in promoting therapeutic resistance. We performed whole genome sequencing (WGS) of BC models and paired primary/metastatic patient samples to identify broader genomic alterations mediated by APOBEC3 activity.
Results: Building on published results, we found that APOBEC3 mutational signatures were highly prevalent in all subtypes of BC and enriched in metastatic hormone receptor-positive (HR+) and triple-negative breast cancers (TNBC) compared to unmatched primary tumors (p < 0.0001 for HR+/HER2-, p < 0.01 for HR+/HER2+ and TNBC). APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ mBC (HR 1.5, 95% CI 1.2 - 1.8, p < 0.001). Expression of APOBEC3A (A3A) and APOBEC3B (A3B) enzymes generated APOBEC3-associated alterations including single nucleotide variants, copy number alterations (CNAs), and clustered mutations in a deamination-dependent manner, and promoted resistance acquisition of estrogen receptor-positive (ER+) BC cells to agents including an ER degrader and CDK4/6 inhibitors. In HER2+ cells, endogenous A3A-driven APOBEC3 activity was also necessary for faster resistance development against anti-HER2 therapies. WGS analyses of resistant models identified CNA events such as loss of heterozygosity in chromosome 13 exclusively in APOBEC3-positive cells. Upon exposure to the CDK4/6 inhibitor abemaciclib, these cells acquired APOBEC3-context truncating mutations in RB1 tumor suppressor gene, a well-characterized mechanism of resistance. Detailed analyses of WGS of five paired patient samples also highlighted acquired resistance-linked alterations such as PIK3CA E54XK mutations in APOBEC3-dominant tumors, which were corroborated in paired pre/post-treatment samples in our clinical cohort. The acquisition of APOBEC3-context alterations in APOBEC3-dominant samples highlights the causality of APOBEC3 mutagenesis in driving resistance-promoting changes. Lastly, comparison of mutational signatures in the paired cohort demonstrated pre-existence of APOBEC3 signatures in 75% of pre-treatment samples that became APOBEC3-dominant post-treatment illustrating that APOBEC3 mutagenesis can be active during early stages of BC.
Conclusions: Our work reveals that APOBEC3 mutational signatures predict poor treatment outcomes of HR+ mBC. We demonstrate that APOBEC3 mutagenesis, primarily through the enzymatic activity of A3A and A3B, drives resistance to endocrine and targeted therapies by causing APOBEC3-context resistance-associated changes. We further show that the presence of APOBEC3 mutagenesis can be detected before therapy exposure and may therefore represent a valuable biomarker and therapeutic target.
Methods: We analyzed SBS mutational signatures in 3,880 BC samples with paired tumor-normal sequencing by the MSK-IMPACT assay using the SigMA algorithm. We utilized the detailed clinical annotation to assess the clinical characteristics of APOBEC3-dominant tumors including survival analyses on endocrine and targeted therapies. We generated cellular models of BC to investigate the molecular drivers of APOBEC3 mutagenesis and its function in promoting therapeutic resistance. We performed whole genome sequencing (WGS) of BC models and paired primary/metastatic patient samples to identify broader genomic alterations mediated by APOBEC3 activity.
Results: Building on published results, we found that APOBEC3 mutational signatures were highly prevalent in all subtypes of BC and enriched in metastatic hormone receptor-positive (HR+) and triple-negative breast cancers (TNBC) compared to unmatched primary tumors (p < 0.0001 for HR+/HER2-, p < 0.01 for HR+/HER2+ and TNBC). APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ mBC (HR 1.5, 95% CI 1.2 - 1.8, p < 0.001). Expression of APOBEC3A (A3A) and APOBEC3B (A3B) enzymes generated APOBEC3-associated alterations including single nucleotide variants, copy number alterations (CNAs), and clustered mutations in a deamination-dependent manner, and promoted resistance acquisition of estrogen receptor-positive (ER+) BC cells to agents including an ER degrader and CDK4/6 inhibitors. In HER2+ cells, endogenous A3A-driven APOBEC3 activity was also necessary for faster resistance development against anti-HER2 therapies. WGS analyses of resistant models identified CNA events such as loss of heterozygosity in chromosome 13 exclusively in APOBEC3-positive cells. Upon exposure to the CDK4/6 inhibitor abemaciclib, these cells acquired APOBEC3-context truncating mutations in RB1 tumor suppressor gene, a well-characterized mechanism of resistance. Detailed analyses of WGS of five paired patient samples also highlighted acquired resistance-linked alterations such as PIK3CA E54XK mutations in APOBEC3-dominant tumors, which were corroborated in paired pre/post-treatment samples in our clinical cohort. The acquisition of APOBEC3-context alterations in APOBEC3-dominant samples highlights the causality of APOBEC3 mutagenesis in driving resistance-promoting changes. Lastly, comparison of mutational signatures in the paired cohort demonstrated pre-existence of APOBEC3 signatures in 75% of pre-treatment samples that became APOBEC3-dominant post-treatment illustrating that APOBEC3 mutagenesis can be active during early stages of BC.
Conclusions: Our work reveals that APOBEC3 mutational signatures predict poor treatment outcomes of HR+ mBC. We demonstrate that APOBEC3 mutagenesis, primarily through the enzymatic activity of A3A and A3B, drives resistance to endocrine and targeted therapies by causing APOBEC3-context resistance-associated changes. We further show that the presence of APOBEC3 mutagenesis can be detected before therapy exposure and may therefore represent a valuable biomarker and therapeutic target.
Background: Large-scale genomic profiling has cataloged the prevalence of single base substitution (SBS) mutational signatures associated with the activity of Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) cytidine deaminases in breast cancer (BC). These mutational signatures are enriched in metastatic BC (mBC) compared to early tumors indicating an association with poor prognosis and a potential function in therapy resistance and disease progression. We sought out to investigate whether APOBEC3 mutational signatures can serve as biomarkers for poor treatment outcomes and if APOBEC3 mutagenesis-driven genomic instability can induce therapy resistance in mBC.
Methods: We analyzed SBS mutational signatures in 3,880 BC samples with paired tumor-normal sequencing by the MSK-IMPACT assay using the SigMA algorithm. We utilized the detailed clinical annotation to assess the clinical characteristics of APOBEC3-dominant tumors including survival analyses on endocrine and targeted therapies. We generated cellular models of BC to investigate the molecular drivers of APOBEC3 mutagenesis and its function in promoting therapeutic resistance. We performed whole genome sequencing (WGS) of BC models and paired primary/metastatic patient samples to identify broader genomic alterations mediated by APOBEC3 activity.
Results: Building on published results, we found that APOBEC3 mutational signatures were highly prevalent in all subtypes of BC and enriched in metastatic hormone receptor-positive (HR+) and triple-negative breast cancers (TNBC) compared to unmatched primary tumors (p < 0.0001 for HR+/HER2-, p < 0.01 for HR+/HER2+ and TNBC). APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ mBC (HR 1.5, 95% CI 1.2 - 1.8, p < 0.001). Expression of APOBEC3A (A3A) and APOBEC3B (A3B) enzymes generated APOBEC3-associated alterations including single nucleotide variants, copy number alterations (CNAs), and clustered mutations in a deamination-dependent manner, and promoted resistance acquisition of estrogen receptor-positive (ER+) BC cells to agents including an ER degrader and CDK4/6 inhibitors. In HER2+ cells, endogenous A3A-driven APOBEC3 activity was also necessary for faster resistance development against anti-HER2 therapies. WGS analyses of resistant models identified CNA events such as loss of heterozygosity in chromosome 13 exclusively in APOBEC3-positive cells. Upon exposure to the CDK4/6 inhibitor abemaciclib, these cells acquired APOBEC3-context truncating mutations in RB1 tumor suppressor gene, a well-characterized mechanism of resistance. Detailed analyses of WGS of five paired patient samples also highlighted acquired resistance-linked alterations such as PIK3CA E54XK mutations in APOBEC3-dominant tumors, which were corroborated in paired pre/post-treatment samples in our clinical cohort. The acquisition of APOBEC3-context alterations in APOBEC3-dominant samples highlights the causality of APOBEC3 mutagenesis in driving resistance-promoting changes. Lastly, comparison of mutational signatures in the paired cohort demonstrated pre-existence of APOBEC3 signatures in 75% of pre-treatment samples that became APOBEC3-dominant post-treatment illustrating that APOBEC3 mutagenesis can be active during early stages of BC.
Conclusions: Our work reveals that APOBEC3 mutational signatures predict poor treatment outcomes of HR+ mBC. We demonstrate that APOBEC3 mutagenesis, primarily through the enzymatic activity of A3A and A3B, drives resistance to endocrine and targeted therapies by causing APOBEC3-context resistance-associated changes. We further show that the presence of APOBEC3 mutagenesis can be detected before therapy exposure and may therefore represent a valuable biomarker and therapeutic target.
Methods: We analyzed SBS mutational signatures in 3,880 BC samples with paired tumor-normal sequencing by the MSK-IMPACT assay using the SigMA algorithm. We utilized the detailed clinical annotation to assess the clinical characteristics of APOBEC3-dominant tumors including survival analyses on endocrine and targeted therapies. We generated cellular models of BC to investigate the molecular drivers of APOBEC3 mutagenesis and its function in promoting therapeutic resistance. We performed whole genome sequencing (WGS) of BC models and paired primary/metastatic patient samples to identify broader genomic alterations mediated by APOBEC3 activity.
Results: Building on published results, we found that APOBEC3 mutational signatures were highly prevalent in all subtypes of BC and enriched in metastatic hormone receptor-positive (HR+) and triple-negative breast cancers (TNBC) compared to unmatched primary tumors (p < 0.0001 for HR+/HER2-, p < 0.01 for HR+/HER2+ and TNBC). APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ mBC (HR 1.5, 95% CI 1.2 - 1.8, p < 0.001). Expression of APOBEC3A (A3A) and APOBEC3B (A3B) enzymes generated APOBEC3-associated alterations including single nucleotide variants, copy number alterations (CNAs), and clustered mutations in a deamination-dependent manner, and promoted resistance acquisition of estrogen receptor-positive (ER+) BC cells to agents including an ER degrader and CDK4/6 inhibitors. In HER2+ cells, endogenous A3A-driven APOBEC3 activity was also necessary for faster resistance development against anti-HER2 therapies. WGS analyses of resistant models identified CNA events such as loss of heterozygosity in chromosome 13 exclusively in APOBEC3-positive cells. Upon exposure to the CDK4/6 inhibitor abemaciclib, these cells acquired APOBEC3-context truncating mutations in RB1 tumor suppressor gene, a well-characterized mechanism of resistance. Detailed analyses of WGS of five paired patient samples also highlighted acquired resistance-linked alterations such as PIK3CA E54XK mutations in APOBEC3-dominant tumors, which were corroborated in paired pre/post-treatment samples in our clinical cohort. The acquisition of APOBEC3-context alterations in APOBEC3-dominant samples highlights the causality of APOBEC3 mutagenesis in driving resistance-promoting changes. Lastly, comparison of mutational signatures in the paired cohort demonstrated pre-existence of APOBEC3 signatures in 75% of pre-treatment samples that became APOBEC3-dominant post-treatment illustrating that APOBEC3 mutagenesis can be active during early stages of BC.
Conclusions: Our work reveals that APOBEC3 mutational signatures predict poor treatment outcomes of HR+ mBC. We demonstrate that APOBEC3 mutagenesis, primarily through the enzymatic activity of A3A and A3B, drives resistance to endocrine and targeted therapies by causing APOBEC3-context resistance-associated changes. We further show that the presence of APOBEC3 mutagenesis can be detected before therapy exposure and may therefore represent a valuable biomarker and therapeutic target.
APOBEC3 mutagenesis induces resistance-promoting genomic alterations in breast cancer
Avantika Gupta
Abstract
Background: Large-scale genomic profiling has cataloged the prevalence of single base substitution (SBS) mutational signatures associated with the activity of Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) cytidine deaminases in breast cancer (BC). These mutational signatures are enriched in metastatic BC (mBC) compared to early tumors indicating an association with poor prognosis and a potential function in therapy resistance and disease progression. We sought out to investigate whether APOBEC3 mutational signatures can serve as biomarkers for poor treatment outcomes and if APOBEC3 mutagenesis-driven genomic instability can induce therapy resistance in mBC.
Methods: We analyzed SBS mutational signatures in 3,880 BC samples with paired tumor-normal sequencing by the MSK-IMPACT assay using the SigMA algorithm. We utilized the detailed clinical annotation to assess the clinical characteristics of APOBEC3-dominant tumors including survival analyses on endocrine and targeted therapies. We generated cellular models of BC to investigate the molecular drivers of APOBEC3 mutagenesis and its function in promoting therapeutic resistance. We performed whole genome sequencing (WGS) of BC models and paired primary/metastatic patient samples to identify broader genomic alterations mediated by APOBEC3 activity.
Results: Building on published results, we found that APOBEC3 mutational signatures were highly prevalent in all subtypes of BC and enriched in metastatic hormone receptor-positive (HR+) and triple-negative breast cancers (TNBC) compared to unmatched primary tumors (p < 0.0001 for HR+/HER2-, p < 0.01 for HR+/HER2+ and TNBC). APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ mBC (HR 1.5, 95% CI 1.2 - 1.8, p < 0.001). Expression of APOBEC3A (A3A) and APOBEC3B (A3B) enzymes generated APOBEC3-associated alterations including single nucleotide variants, copy number alterations (CNAs), and clustered mutations in a deamination-dependent manner, and promoted resistance acquisition of estrogen receptor-positive (ER+) BC cells to agents including an ER degrader and CDK4/6 inhibitors. In HER2+ cells, endogenous A3A-driven APOBEC3 activity was also necessary for faster resistance development against anti-HER2 therapies. WGS analyses of resistant models identified CNA events such as loss of heterozygosity in chromosome 13 exclusively in APOBEC3-positive cells. Upon exposure to the CDK4/6 inhibitor abemaciclib, these cells acquired APOBEC3-context truncating mutations in RB1 tumor suppressor gene, a well-characterized mechanism of resistance. Detailed analyses of WGS of five paired patient samples also highlighted acquired resistance-linked alterations such as PIK3CA E54XK mutations in APOBEC3-dominant tumors, which were corroborated in paired pre/post-treatment samples in our clinical cohort. The acquisition of APOBEC3-context alterations in APOBEC3-dominant samples highlights the causality of APOBEC3 mutagenesis in driving resistance-promoting changes. Lastly, comparison of mutational signatures in the paired cohort demonstrated pre-existence of APOBEC3 signatures in 75% of pre-treatment samples that became APOBEC3-dominant post-treatment illustrating that APOBEC3 mutagenesis can be active during early stages of BC.
Conclusions: Our work reveals that APOBEC3 mutational signatures predict poor treatment outcomes of HR+ mBC. We demonstrate that APOBEC3 mutagenesis, primarily through the enzymatic activity of A3A and A3B, drives resistance to endocrine and targeted therapies by causing APOBEC3-context resistance-associated changes. We further show that the presence of APOBEC3 mutagenesis can be detected before therapy exposure and may therefore represent a valuable biomarker and therapeutic target.
Methods: We analyzed SBS mutational signatures in 3,880 BC samples with paired tumor-normal sequencing by the MSK-IMPACT assay using the SigMA algorithm. We utilized the detailed clinical annotation to assess the clinical characteristics of APOBEC3-dominant tumors including survival analyses on endocrine and targeted therapies. We generated cellular models of BC to investigate the molecular drivers of APOBEC3 mutagenesis and its function in promoting therapeutic resistance. We performed whole genome sequencing (WGS) of BC models and paired primary/metastatic patient samples to identify broader genomic alterations mediated by APOBEC3 activity.
Results: Building on published results, we found that APOBEC3 mutational signatures were highly prevalent in all subtypes of BC and enriched in metastatic hormone receptor-positive (HR+) and triple-negative breast cancers (TNBC) compared to unmatched primary tumors (p < 0.0001 for HR+/HER2-, p < 0.01 for HR+/HER2+ and TNBC). APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ mBC (HR 1.5, 95% CI 1.2 - 1.8, p < 0.001). Expression of APOBEC3A (A3A) and APOBEC3B (A3B) enzymes generated APOBEC3-associated alterations including single nucleotide variants, copy number alterations (CNAs), and clustered mutations in a deamination-dependent manner, and promoted resistance acquisition of estrogen receptor-positive (ER+) BC cells to agents including an ER degrader and CDK4/6 inhibitors. In HER2+ cells, endogenous A3A-driven APOBEC3 activity was also necessary for faster resistance development against anti-HER2 therapies. WGS analyses of resistant models identified CNA events such as loss of heterozygosity in chromosome 13 exclusively in APOBEC3-positive cells. Upon exposure to the CDK4/6 inhibitor abemaciclib, these cells acquired APOBEC3-context truncating mutations in RB1 tumor suppressor gene, a well-characterized mechanism of resistance. Detailed analyses of WGS of five paired patient samples also highlighted acquired resistance-linked alterations such as PIK3CA E54XK mutations in APOBEC3-dominant tumors, which were corroborated in paired pre/post-treatment samples in our clinical cohort. The acquisition of APOBEC3-context alterations in APOBEC3-dominant samples highlights the causality of APOBEC3 mutagenesis in driving resistance-promoting changes. Lastly, comparison of mutational signatures in the paired cohort demonstrated pre-existence of APOBEC3 signatures in 75% of pre-treatment samples that became APOBEC3-dominant post-treatment illustrating that APOBEC3 mutagenesis can be active during early stages of BC.
Conclusions: Our work reveals that APOBEC3 mutational signatures predict poor treatment outcomes of HR+ mBC. We demonstrate that APOBEC3 mutagenesis, primarily through the enzymatic activity of A3A and A3B, drives resistance to endocrine and targeted therapies by causing APOBEC3-context resistance-associated changes. We further show that the presence of APOBEC3 mutagenesis can be detected before therapy exposure and may therefore represent a valuable biomarker and therapeutic target.
Background: Large-scale genomic profiling has cataloged the prevalence of single base substitution (SBS) mutational signatures associated with the activity of Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) cytidine deaminases in breast cancer (BC). These mutational signatures are enriched in metastatic BC (mBC) compared to early tumors indicating an association with poor prognosis and a potential function in therapy resistance and disease progression. We sought out to investigate whether APOBEC3 mutational signatures can serve as biomarkers for poor treatment outcomes and if APOBEC3 mutagenesis-driven genomic instability can induce therapy resistance in mBC.
Methods: We analyzed SBS mutational signatures in 3,880 BC samples with paired tumor-normal sequencing by the MSK-IMPACT assay using the SigMA algorithm. We utilized the detailed clinical annotation to assess the clinical characteristics of APOBEC3-dominant tumors including survival analyses on endocrine and targeted therapies. We generated cellular models of BC to investigate the molecular drivers of APOBEC3 mutagenesis and its function in promoting therapeutic resistance. We performed whole genome sequencing (WGS) of BC models and paired primary/metastatic patient samples to identify broader genomic alterations mediated by APOBEC3 activity.
Results: Building on published results, we found that APOBEC3 mutational signatures were highly prevalent in all subtypes of BC and enriched in metastatic hormone receptor-positive (HR+) and triple-negative breast cancers (TNBC) compared to unmatched primary tumors (p < 0.0001 for HR+/HER2-, p < 0.01 for HR+/HER2+ and TNBC). APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ mBC (HR 1.5, 95% CI 1.2 - 1.8, p < 0.001). Expression of APOBEC3A (A3A) and APOBEC3B (A3B) enzymes generated APOBEC3-associated alterations including single nucleotide variants, copy number alterations (CNAs), and clustered mutations in a deamination-dependent manner, and promoted resistance acquisition of estrogen receptor-positive (ER+) BC cells to agents including an ER degrader and CDK4/6 inhibitors. In HER2+ cells, endogenous A3A-driven APOBEC3 activity was also necessary for faster resistance development against anti-HER2 therapies. WGS analyses of resistant models identified CNA events such as loss of heterozygosity in chromosome 13 exclusively in APOBEC3-positive cells. Upon exposure to the CDK4/6 inhibitor abemaciclib, these cells acquired APOBEC3-context truncating mutations in RB1 tumor suppressor gene, a well-characterized mechanism of resistance. Detailed analyses of WGS of five paired patient samples also highlighted acquired resistance-linked alterations such as PIK3CA E54XK mutations in APOBEC3-dominant tumors, which were corroborated in paired pre/post-treatment samples in our clinical cohort. The acquisition of APOBEC3-context alterations in APOBEC3-dominant samples highlights the causality of APOBEC3 mutagenesis in driving resistance-promoting changes. Lastly, comparison of mutational signatures in the paired cohort demonstrated pre-existence of APOBEC3 signatures in 75% of pre-treatment samples that became APOBEC3-dominant post-treatment illustrating that APOBEC3 mutagenesis can be active during early stages of BC.
Conclusions: Our work reveals that APOBEC3 mutational signatures predict poor treatment outcomes of HR+ mBC. We demonstrate that APOBEC3 mutagenesis, primarily through the enzymatic activity of A3A and A3B, drives resistance to endocrine and targeted therapies by causing APOBEC3-context resistance-associated changes. We further show that the presence of APOBEC3 mutagenesis can be detected before therapy exposure and may therefore represent a valuable biomarker and therapeutic target.
Methods: We analyzed SBS mutational signatures in 3,880 BC samples with paired tumor-normal sequencing by the MSK-IMPACT assay using the SigMA algorithm. We utilized the detailed clinical annotation to assess the clinical characteristics of APOBEC3-dominant tumors including survival analyses on endocrine and targeted therapies. We generated cellular models of BC to investigate the molecular drivers of APOBEC3 mutagenesis and its function in promoting therapeutic resistance. We performed whole genome sequencing (WGS) of BC models and paired primary/metastatic patient samples to identify broader genomic alterations mediated by APOBEC3 activity.
Results: Building on published results, we found that APOBEC3 mutational signatures were highly prevalent in all subtypes of BC and enriched in metastatic hormone receptor-positive (HR+) and triple-negative breast cancers (TNBC) compared to unmatched primary tumors (p < 0.0001 for HR+/HER2-, p < 0.01 for HR+/HER2+ and TNBC). APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ mBC (HR 1.5, 95% CI 1.2 - 1.8, p < 0.001). Expression of APOBEC3A (A3A) and APOBEC3B (A3B) enzymes generated APOBEC3-associated alterations including single nucleotide variants, copy number alterations (CNAs), and clustered mutations in a deamination-dependent manner, and promoted resistance acquisition of estrogen receptor-positive (ER+) BC cells to agents including an ER degrader and CDK4/6 inhibitors. In HER2+ cells, endogenous A3A-driven APOBEC3 activity was also necessary for faster resistance development against anti-HER2 therapies. WGS analyses of resistant models identified CNA events such as loss of heterozygosity in chromosome 13 exclusively in APOBEC3-positive cells. Upon exposure to the CDK4/6 inhibitor abemaciclib, these cells acquired APOBEC3-context truncating mutations in RB1 tumor suppressor gene, a well-characterized mechanism of resistance. Detailed analyses of WGS of five paired patient samples also highlighted acquired resistance-linked alterations such as PIK3CA E54XK mutations in APOBEC3-dominant tumors, which were corroborated in paired pre/post-treatment samples in our clinical cohort. The acquisition of APOBEC3-context alterations in APOBEC3-dominant samples highlights the causality of APOBEC3 mutagenesis in driving resistance-promoting changes. Lastly, comparison of mutational signatures in the paired cohort demonstrated pre-existence of APOBEC3 signatures in 75% of pre-treatment samples that became APOBEC3-dominant post-treatment illustrating that APOBEC3 mutagenesis can be active during early stages of BC.
Conclusions: Our work reveals that APOBEC3 mutational signatures predict poor treatment outcomes of HR+ mBC. We demonstrate that APOBEC3 mutagenesis, primarily through the enzymatic activity of A3A and A3B, drives resistance to endocrine and targeted therapies by causing APOBEC3-context resistance-associated changes. We further show that the presence of APOBEC3 mutagenesis can be detected before therapy exposure and may therefore represent a valuable biomarker and therapeutic target.
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