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Name:
<i>NRG1</i> fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents
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<i>NRG1</i> fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents
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T00H12M49S
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https://cadmoreoriginalmedia.blob.core.windows.net/44e7af10-47f1-4941-8e96-cf5c51d28337/Nrg1 Review - V15.mp4?sv=2019-02-02&sr=c&sig=%2F3xB3mijei4KwCubiVAdlb%2FxKn%2FAWpLPeGlybz5xkS4%3D&st=2024-12-03T17%3A11%3A48Z&se=2024-12-03T19%3A16%3A48Z&sp=r
Upload Date:
2023-03-14T00:00:00.0000000
Transcript:
Language: EN.
Segment:0 .
[MUSIC PLAYING]
SPEAKER: On behalf of Dr. Stephen Liu, Georgetown University Medical Center Washington, USA, and his co-authors, this video summarizes the review article entitled NRG1 fusion-driven tumors2 biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents, which was recently published in Annals of Oncology. This comprehensive narrative review addresses and highlights several key points, including that NRG1 fusions result in ErbB-mediated pathway activation and present a rational therapeutic target.
SPEAKER: ErbB-targeted treatments, such as afatinib, can be effective therapeutic options in tumors harboring NRG1 fusions. And NRG1 fusion-driven cancers are rare with a prevalence of under 1%. However, in some tumor subtypes, the prevalence is higher. For instance, around 10% to 30% of cases of invasive mucinous adenocarcinoma, IMA, of the lung display NRG1 fusions.
SPEAKER: There also seems to be a higher prevalence in KRAS wild-type pancreatic ductal adenocarcinoma. [MUSIC PLAYING] The aim of this narrative review is to provide information on the biology, detection, and incidence of NRG1 fusions, their role in the development of certain types of cancer, and potential intervention modalities that target the ErbB pathway.
SPEAKER: Among these potential targeted therapeutic interventions, afatinib has been used most frequently in a clinical context for the treatment of NRG1 fusion-driven tumors. [MUSIC PLAYING] To identify relevant published data on NRG1 and NRG1 gene fusions, we conducted literature searches of PubMed using search terms "neuregulin-1" and "afatinib", and "gene fusion", and "NRG1 fusion".
SPEAKER: We also searched Google Scholar, as well as conference proceedings from recent major congresses including ASCO, ESMO, AACR, and WCLC. Searches were last updated in mid-March of 2020. [MUSIC PLAYING] First, we review the biology of NRG1 and NRG1 fusions, which is complex. Briefly, gene fusions are hybrid genes that result from structural DNA rearrangements, including translocations and insertions, transcription read through or splicing.
SPEAKER: In a healthy cell, there's normal expression of the NRG1 protein, controlled cell signaling, and normal cell growth and replication. However, in a cell with an NRG1 fusion, such as CD74-NRG1, there's increased cell signaling, growth, and replication, which is a potential protumoral mechanism for the development of cancer. NRG1 fusions result in aberrant expression of the EGF-like domain of NRG1 on the cell surface, which serves as a ligand for ErbB3 and ErbB4, also known as HER3 and HER4, and induces the formation of heterodimers most frequently ErbB2 and ErbB3, but also with EGFR and ErbB4.
SPEAKER: This leads to pathologic activation of PI3K/Akt, MAPK, and other signaling pathways resulting in abnormal cell proliferation. The circled A towards the bottom left of this figure, shows how the wild-type NRG1 protein may be cleaved by proteases to release soluble NRG1 containing the EGF-like region. Soluble NRG1 diffuses to activate distant ErbB3 or ErbB4 receptor subunits, this is paracrine signaling.
SPEAKER: Activated receptors then lead to the formation of heterodimers. Just to the right, the circled B shows how excess NRG1 can become tethered to the cell surface as NRG1 fusion proteins may have reduced cleavage sites and become poorer substrates for proteases. Next, the circled C shows how NRG1 fusion proteins holds the EGF-like domain close to the cell surface causing uncontrolled juxtacrine signaling. Aberrant NRG1 signaling drive cell proliferation and avoidance of apoptosis via PI3K and RAS-dependent signaling, and activation of downstream signaling molecules.
SPEAKER: And finally, the circled D in this figure shows that NRG1 fusion proteins may also drive autocrine signaling via the same PI3K and RAS-dependent pathways. The combination of overexpression and the higher affinity EGF-like domain results in greater protumoral potential. The most common NRG1 fusion partner is CD74 although numerous fusion partners have been identified.
SPEAKER: This figure provides a schematic of the wild-type NRG1 gene at the top, and the most common NRG1 fusion partners below. The dotted line indicates the point at which NRG1 and the fusion partner are joined, and the EGF-like region is shown in purple. [MUSIC PLAYING] Next, we review the role of NRG1 fusions in cancer.
SPEAKER: Characterization of the CD74-NRG1 fusion protein provided insight into the protumoral effects of NRG1 fusions. Fernandez-Cuesta and colleagues demonstrated that the EGF-like domain of the fusion proteins was overexpressed on the cell surface, and it was hypothesized and subsequently confirmed that NRG1 fusions promote signaling through ErbB2 and ErbB3 heterodimers.
SPEAKER: It's been consistently reported in different cancer types and with different NRG1 fusions that ErbB2 and ErbB3 heterodimers activate signaling through both the PI3K/Akt pathway and the MAPK pathway with phosphorylation of PI3K/Akt and mTOR being observed as well as ERK. Another proposed protumoral mechanism of NRG1 fusions is that they confer cancer stem cell-like properties, including sphericalization on immature progenitor-like cells.
SPEAKER: The CD74-NRG1 fusion not only induced sphere-forming ability, in vitro, but also enhanced the tumor-initiating ability, in vivo, suggesting that the fusion gene could be involved in tumor development by inducing cancer stem cell-like properties. Overexpression of CD74-NRG1 has also been shown to induce epithelial-to-mesenchymal transition, EMT, as demonstrated by increased VIM and SNAIL protein expression, and decreased CDH1 levels.
SPEAKER: Microarray analysis identified overexpression of EMT markers, SRC and ErbB pathways, and underexpression of cell adhesion markers supporting an oncogenic phenotype. In addition, isoforms of NRG1 with the beta isoform of the EGF-like domain have higher affinity for the receptors than those with the alpha isoform. Therefore, the combination of overexpression and higher affinity EGF-like domain may produce greater protumoral potential.
SPEAKER: [MUSIC PLAYING] Until recently, fusion proteins and genes in solid tumors were detected primarily using IHC and FISH techniques. Important advances in gene fusion detection include DNA next-generation sequencing, and the introduction of targeted gene fusion panels on RNA. Each detection technique has advantages and disadvantages. NRG1 is a very large gene, mostly comprised of noncoding intronic regions making detection with DNA-based techniques challenging.
SPEAKER: RNA sequencing is more reliable than DNA NGS at detecting most NRG1 fusions. The unidirectional targeted approach of RNA sequencing allows the detection of unknown fusion partners, which will be particularly useful in light of the variability of NRG1 fusion partners. In general, NRG1 fusions are rare across different types of cancer, typically occurring in less than 1% in most reported series.
SPEAKER: However, NRG1 fusions appear to be more common in patients with IMA of the lung, generally in the range of about 10% to 30%. In patients with IMA, it was thought that NRG1 fusions were mutually exclusive with KRAS mutations, however, a growing number of studies have shown this may not be the case, whereas it appears that almost all patients with pancreatic ductal adenocarcinoma harboring NRG1 fusions are KRAS wild-type.
SPEAKER: Also noteworthy is that recent NRG1 registry data indicate that a substantial proportion, approximately 20% of NRG1 fusion positive non-small-cell lung cancer cases are non-mucinous adenocarcinomas. And while outcomes with standard therapy are suboptimal, the prognostic value of NRG1 fusions is still unclear. NRG1 fusions are rare, but with the emergence of other tumor agnostic drivers, the best detection strategy involves the wider implementation of comprehensive genomic profiling.
SPEAKER: [MUSIC PLAYING] And finally, we review potential treatments targeting the NRG1/ErbB pathway. Since NRG1 proteins are ligands of ErbB receptors, ErbB-targeted treatments are of particular interest. For example, afatinib downregulates ErbB signaling by binding to the kinase domains of EGFR, ErbB2, and ErbB4.
SPEAKER: And irreversibly inhibiting tyrosine kinase autophosphorylation. Various preclinical studies and clinical case reports provide evidence of activity of afatinib and other small molecules, such as lapatinib, as well as some monoclonal antibodies. To date, the most frequently reported agent showing clinical evidence of response to ErbB inhibition in patients with NRG1 fusion positive tumors has been afatinib, although reports of its efficacy in this setting are currently limited to case reports in patients with IMA with partial responses of up to 10 months, pancreatic ductal adenocarcinoma, lung adenocarcinoma, ovarian cancer, and cholangiocarcinoma.
SPEAKER: In addition, a recently developed global registry of patients with NRG1 fusion-positive non-small-cell lung cancer indicates that 4 of 12 patients treated with afatinib had a partial response or stable disease. Also of interest is that activation of NRG1 fusion-driven pathways may act as a mechanism of resistance following treatment with certain tyrosine kinase inhibitors, including ALK inhibitors, such as crizotinib.
SPEAKER: [MUSIC PLAYING] This comprehensive review of NRG1 fusion-driven tumors highlights that existing ErbB-targeted treatments have potential as targeted therapies in tumors harboring NRG1 fusions. As the implementation of more broad spectrum genomic and transcriptomic sequencing approaches becomes more common, the number of niche opportunities for targeting cancers expands.
SPEAKER: The growing number of targetable cancer-driving fusions is an example of the changing landscape of cancer therapy. While tumors with NRG1 fusions do not represent a substantial proportion of cancers overall, the emerging evidence supports the use of existing anticancer agents effectively repurposed to target these cancer drivers. [MUSIC PLAYING]
Segment:0 .
[MUSIC PLAYING]
SPEAKER: On behalf of Dr. Stephen Liu, Georgetown University Medical Center Washington, USA, and his co-authors, this video summarizes the review article entitled NRG1 fusion-driven tumors2 biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents, which was recently published in Annals of Oncology. This comprehensive narrative review addresses and highlights several key points, including that NRG1 fusions result in ErbB-mediated pathway activation and present a rational therapeutic target.
SPEAKER: ErbB-targeted treatments, such as afatinib, can be effective therapeutic options in tumors harboring NRG1 fusions. And NRG1 fusion-driven cancers are rare with a prevalence of under 1%. However, in some tumor subtypes, the prevalence is higher. For instance, around 10% to 30% of cases of invasive mucinous adenocarcinoma, IMA, of the lung display NRG1 fusions.
SPEAKER: There also seems to be a higher prevalence in KRAS wild-type pancreatic ductal adenocarcinoma. [MUSIC PLAYING] The aim of this narrative review is to provide information on the biology, detection, and incidence of NRG1 fusions, their role in the development of certain types of cancer, and potential intervention modalities that target the ErbB pathway.
SPEAKER: Among these potential targeted therapeutic interventions, afatinib has been used most frequently in a clinical context for the treatment of NRG1 fusion-driven tumors. [MUSIC PLAYING] To identify relevant published data on NRG1 and NRG1 gene fusions, we conducted literature searches of PubMed using search terms "neuregulin-1" and "afatinib", and "gene fusion", and "NRG1 fusion".
SPEAKER: We also searched Google Scholar, as well as conference proceedings from recent major congresses including ASCO, ESMO, AACR, and WCLC. Searches were last updated in mid-March of 2020. [MUSIC PLAYING] First, we review the biology of NRG1 and NRG1 fusions, which is complex. Briefly, gene fusions are hybrid genes that result from structural DNA rearrangements, including translocations and insertions, transcription read through or splicing.
SPEAKER: In a healthy cell, there's normal expression of the NRG1 protein, controlled cell signaling, and normal cell growth and replication. However, in a cell with an NRG1 fusion, such as CD74-NRG1, there's increased cell signaling, growth, and replication, which is a potential protumoral mechanism for the development of cancer. NRG1 fusions result in aberrant expression of the EGF-like domain of NRG1 on the cell surface, which serves as a ligand for ErbB3 and ErbB4, also known as HER3 and HER4, and induces the formation of heterodimers most frequently ErbB2 and ErbB3, but also with EGFR and ErbB4.
SPEAKER: This leads to pathologic activation of PI3K/Akt, MAPK, and other signaling pathways resulting in abnormal cell proliferation. The circled A towards the bottom left of this figure, shows how the wild-type NRG1 protein may be cleaved by proteases to release soluble NRG1 containing the EGF-like region. Soluble NRG1 diffuses to activate distant ErbB3 or ErbB4 receptor subunits, this is paracrine signaling.
SPEAKER: Activated receptors then lead to the formation of heterodimers. Just to the right, the circled B shows how excess NRG1 can become tethered to the cell surface as NRG1 fusion proteins may have reduced cleavage sites and become poorer substrates for proteases. Next, the circled C shows how NRG1 fusion proteins holds the EGF-like domain close to the cell surface causing uncontrolled juxtacrine signaling. Aberrant NRG1 signaling drive cell proliferation and avoidance of apoptosis via PI3K and RAS-dependent signaling, and activation of downstream signaling molecules.
SPEAKER: And finally, the circled D in this figure shows that NRG1 fusion proteins may also drive autocrine signaling via the same PI3K and RAS-dependent pathways. The combination of overexpression and the higher affinity EGF-like domain results in greater protumoral potential. The most common NRG1 fusion partner is CD74 although numerous fusion partners have been identified.
SPEAKER: This figure provides a schematic of the wild-type NRG1 gene at the top, and the most common NRG1 fusion partners below. The dotted line indicates the point at which NRG1 and the fusion partner are joined, and the EGF-like region is shown in purple. [MUSIC PLAYING] Next, we review the role of NRG1 fusions in cancer.
SPEAKER: Characterization of the CD74-NRG1 fusion protein provided insight into the protumoral effects of NRG1 fusions. Fernandez-Cuesta and colleagues demonstrated that the EGF-like domain of the fusion proteins was overexpressed on the cell surface, and it was hypothesized and subsequently confirmed that NRG1 fusions promote signaling through ErbB2 and ErbB3 heterodimers.
SPEAKER: It's been consistently reported in different cancer types and with different NRG1 fusions that ErbB2 and ErbB3 heterodimers activate signaling through both the PI3K/Akt pathway and the MAPK pathway with phosphorylation of PI3K/Akt and mTOR being observed as well as ERK. Another proposed protumoral mechanism of NRG1 fusions is that they confer cancer stem cell-like properties, including sphericalization on immature progenitor-like cells.
SPEAKER: The CD74-NRG1 fusion not only induced sphere-forming ability, in vitro, but also enhanced the tumor-initiating ability, in vivo, suggesting that the fusion gene could be involved in tumor development by inducing cancer stem cell-like properties. Overexpression of CD74-NRG1 has also been shown to induce epithelial-to-mesenchymal transition, EMT, as demonstrated by increased VIM and SNAIL protein expression, and decreased CDH1 levels.
SPEAKER: Microarray analysis identified overexpression of EMT markers, SRC and ErbB pathways, and underexpression of cell adhesion markers supporting an oncogenic phenotype. In addition, isoforms of NRG1 with the beta isoform of the EGF-like domain have higher affinity for the receptors than those with the alpha isoform. Therefore, the combination of overexpression and higher affinity EGF-like domain may produce greater protumoral potential.
SPEAKER: [MUSIC PLAYING] Until recently, fusion proteins and genes in solid tumors were detected primarily using IHC and FISH techniques. Important advances in gene fusion detection include DNA next-generation sequencing, and the introduction of targeted gene fusion panels on RNA. Each detection technique has advantages and disadvantages. NRG1 is a very large gene, mostly comprised of noncoding intronic regions making detection with DNA-based techniques challenging.
SPEAKER: RNA sequencing is more reliable than DNA NGS at detecting most NRG1 fusions. The unidirectional targeted approach of RNA sequencing allows the detection of unknown fusion partners, which will be particularly useful in light of the variability of NRG1 fusion partners. In general, NRG1 fusions are rare across different types of cancer, typically occurring in less than 1% in most reported series.
SPEAKER: However, NRG1 fusions appear to be more common in patients with IMA of the lung, generally in the range of about 10% to 30%. In patients with IMA, it was thought that NRG1 fusions were mutually exclusive with KRAS mutations, however, a growing number of studies have shown this may not be the case, whereas it appears that almost all patients with pancreatic ductal adenocarcinoma harboring NRG1 fusions are KRAS wild-type.
SPEAKER: Also noteworthy is that recent NRG1 registry data indicate that a substantial proportion, approximately 20% of NRG1 fusion positive non-small-cell lung cancer cases are non-mucinous adenocarcinomas. And while outcomes with standard therapy are suboptimal, the prognostic value of NRG1 fusions is still unclear. NRG1 fusions are rare, but with the emergence of other tumor agnostic drivers, the best detection strategy involves the wider implementation of comprehensive genomic profiling.
SPEAKER: [MUSIC PLAYING] And finally, we review potential treatments targeting the NRG1/ErbB pathway. Since NRG1 proteins are ligands of ErbB receptors, ErbB-targeted treatments are of particular interest. For example, afatinib downregulates ErbB signaling by binding to the kinase domains of EGFR, ErbB2, and ErbB4.
SPEAKER: And irreversibly inhibiting tyrosine kinase autophosphorylation. Various preclinical studies and clinical case reports provide evidence of activity of afatinib and other small molecules, such as lapatinib, as well as some monoclonal antibodies. To date, the most frequently reported agent showing clinical evidence of response to ErbB inhibition in patients with NRG1 fusion positive tumors has been afatinib, although reports of its efficacy in this setting are currently limited to case reports in patients with IMA with partial responses of up to 10 months, pancreatic ductal adenocarcinoma, lung adenocarcinoma, ovarian cancer, and cholangiocarcinoma.
SPEAKER: In addition, a recently developed global registry of patients with NRG1 fusion-positive non-small-cell lung cancer indicates that 4 of 12 patients treated with afatinib had a partial response or stable disease. Also of interest is that activation of NRG1 fusion-driven pathways may act as a mechanism of resistance following treatment with certain tyrosine kinase inhibitors, including ALK inhibitors, such as crizotinib.
SPEAKER: [MUSIC PLAYING] This comprehensive review of NRG1 fusion-driven tumors highlights that existing ErbB-targeted treatments have potential as targeted therapies in tumors harboring NRG1 fusions. As the implementation of more broad spectrum genomic and transcriptomic sequencing approaches becomes more common, the number of niche opportunities for targeting cancers expands.
SPEAKER: The growing number of targetable cancer-driving fusions is an example of the changing landscape of cancer therapy. While tumors with NRG1 fusions do not represent a substantial proportion of cancers overall, the emerging evidence supports the use of existing anticancer agents effectively repurposed to target these cancer drivers. [MUSIC PLAYING]
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