Nanocage-incorporated engineered destabilized 3'UTR ARE of ERBB2 inhibits tumor growth and liver and lung metastasis in EGFR T790M osimertinib- and trastuzumab-resistant and ERBB2-expressing NSCLC via the reduction of ERBB2
Non-small cell lung cancer (NSCLC) caused more deaths in 2017 than breast cancer, prostate, and brain cancers combined. This is primarily due to their aggressive metastatic nature, leading to more fatal rates of cancer patients. Despite this condition, there are no clinically approved drugs that can...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-04-01
|
| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2024.1344852/full |
| _version_ | 1827278487673634816 |
|---|---|
| author | Chidiebere U. Awah Chidiebere U. Awah Joo Sun Mun Aloka Paragodaarachchi Aloka Paragodaarachchi Baris Boylu Martin Nzegwu Hiroshi Matsui Hiroshi Matsui Hiroshi Matsui Hiroshi Matsui Olorunseun Ogunwobi Olorunseun Ogunwobi Olorunseun Ogunwobi |
| author_facet | Chidiebere U. Awah Chidiebere U. Awah Joo Sun Mun Aloka Paragodaarachchi Aloka Paragodaarachchi Baris Boylu Martin Nzegwu Hiroshi Matsui Hiroshi Matsui Hiroshi Matsui Hiroshi Matsui Olorunseun Ogunwobi Olorunseun Ogunwobi Olorunseun Ogunwobi |
| author_sort | Chidiebere U. Awah |
| collection | DOAJ |
| description | Non-small cell lung cancer (NSCLC) caused more deaths in 2017 than breast cancer, prostate, and brain cancers combined. This is primarily due to their aggressive metastatic nature, leading to more fatal rates of cancer patients. Despite this condition, there are no clinically approved drugs that can target metastasis. The NSCLC with EGFR T790M-overexpressing HER2 shows the resistance to osimertinib and trastuzumab starting 10–18 months after the therapy, and thus prospects are grim to these patients. To target the recalcitrant ERBB2 driver oncogene, we developed two engineered destabilizing 3'UTR ERBB2 constructs that degrade the endogenous ERBB2 transcript and proteins by overwriting the encoded endogenous ERBB2 mRNA with the destabilizing message. When iron oxide nanocages (IO nanocages) were used as vehicles to deliver them to tumors and whole tissues in mice bearing tumors, it was well tolerated and safe and caused no genome rearrangement whereas they were integrated into genome deserts (non-coding regions). We achieved significant reduction of the primary tumor volume with desARE3'UTRERBB2-30, achieving 50% complete tumor lysis and inhibiting 60%–80% of liver metastasis, hepatomegaly, and 90% of lung metastasis, through ERBB2 downregulation. These constructs were distributed robustly into tumors, livers, lungs, kidneys, and spleen and mildly in the brain and not in the heart. They caused no abnormality in both short- and long-term administrations as well as in healthy mice. In summary, we accomplished significant breakthrough for the therapeutics of intractable lung cancer patients whose cancers become resistant and metastasize. |
| first_indexed | 2024-04-24T07:58:40Z |
| format | Article |
| id | doaj.art-d0be878fbec7454e8fe5d7d025ee83e3 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-24T07:58:40Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-d0be878fbec7454e8fe5d7d025ee83e32024-04-18T04:31:48ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2024-04-011410.3389/fonc.2024.13448521344852Nanocage-incorporated engineered destabilized 3'UTR ARE of ERBB2 inhibits tumor growth and liver and lung metastasis in EGFR T790M osimertinib- and trastuzumab-resistant and ERBB2-expressing NSCLC via the reduction of ERBB2Chidiebere U. Awah0Chidiebere U. Awah1Joo Sun Mun2Aloka Paragodaarachchi3Aloka Paragodaarachchi4Baris Boylu5Martin Nzegwu6Hiroshi Matsui7Hiroshi Matsui8Hiroshi Matsui9Hiroshi Matsui10Olorunseun Ogunwobi11Olorunseun Ogunwobi12Olorunseun Ogunwobi13Department of Biological Sciences, Hunter College of The City University of New York, New York, NY, United StatesJoan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United StatesDepartment of Chemistry, Hunter College, City University of New York, New York, NY, United StatesDepartment of Chemistry, Hunter College, City University of New York, New York, NY, United StatesPh.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY, United StatesDepartment of Biological Sciences, Hunter College of The City University of New York, New York, NY, United StatesDepartment of Pathology, University of Tulane School of Medicine, New Orleans, LA, United StatesDepartment of Chemistry, Hunter College, City University of New York, New York, NY, United StatesPh.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY, United StatesPh.D. Program in Chemistry, The Graduate Center of City University of New York, New York, NY, United StatesDepartment of Biochemistry, Weill Cornell Medical College, New York, NY, United StatesDepartment of Biological Sciences, Hunter College of The City University of New York, New York, NY, United StatesJoan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United StatesHunter College for Cancer Health Disparities Research, Hunter College of The City University of New York, New York, NY, United StatesNon-small cell lung cancer (NSCLC) caused more deaths in 2017 than breast cancer, prostate, and brain cancers combined. This is primarily due to their aggressive metastatic nature, leading to more fatal rates of cancer patients. Despite this condition, there are no clinically approved drugs that can target metastasis. The NSCLC with EGFR T790M-overexpressing HER2 shows the resistance to osimertinib and trastuzumab starting 10–18 months after the therapy, and thus prospects are grim to these patients. To target the recalcitrant ERBB2 driver oncogene, we developed two engineered destabilizing 3'UTR ERBB2 constructs that degrade the endogenous ERBB2 transcript and proteins by overwriting the encoded endogenous ERBB2 mRNA with the destabilizing message. When iron oxide nanocages (IO nanocages) were used as vehicles to deliver them to tumors and whole tissues in mice bearing tumors, it was well tolerated and safe and caused no genome rearrangement whereas they were integrated into genome deserts (non-coding regions). We achieved significant reduction of the primary tumor volume with desARE3'UTRERBB2-30, achieving 50% complete tumor lysis and inhibiting 60%–80% of liver metastasis, hepatomegaly, and 90% of lung metastasis, through ERBB2 downregulation. These constructs were distributed robustly into tumors, livers, lungs, kidneys, and spleen and mildly in the brain and not in the heart. They caused no abnormality in both short- and long-term administrations as well as in healthy mice. In summary, we accomplished significant breakthrough for the therapeutics of intractable lung cancer patients whose cancers become resistant and metastasize.https://www.frontiersin.org/articles/10.3389/fonc.2024.1344852/fullNSCLC EGFRT790MERBB2/HER2osimertinib and trastuzumab resistanceengineered mRNA destabilizationmRNA overwritingiron oxide nanocages (IO) |
| spellingShingle | Chidiebere U. Awah Chidiebere U. Awah Joo Sun Mun Aloka Paragodaarachchi Aloka Paragodaarachchi Baris Boylu Martin Nzegwu Hiroshi Matsui Hiroshi Matsui Hiroshi Matsui Hiroshi Matsui Olorunseun Ogunwobi Olorunseun Ogunwobi Olorunseun Ogunwobi Nanocage-incorporated engineered destabilized 3'UTR ARE of ERBB2 inhibits tumor growth and liver and lung metastasis in EGFR T790M osimertinib- and trastuzumab-resistant and ERBB2-expressing NSCLC via the reduction of ERBB2 Frontiers in Oncology NSCLC EGFRT790M ERBB2/HER2 osimertinib and trastuzumab resistance engineered mRNA destabilization mRNA overwriting iron oxide nanocages (IO) |
| title | Nanocage-incorporated engineered destabilized 3'UTR ARE of ERBB2 inhibits tumor growth and liver and lung metastasis in EGFR T790M osimertinib- and trastuzumab-resistant and ERBB2-expressing NSCLC via the reduction of ERBB2 |
| title_full | Nanocage-incorporated engineered destabilized 3'UTR ARE of ERBB2 inhibits tumor growth and liver and lung metastasis in EGFR T790M osimertinib- and trastuzumab-resistant and ERBB2-expressing NSCLC via the reduction of ERBB2 |
| title_fullStr | Nanocage-incorporated engineered destabilized 3'UTR ARE of ERBB2 inhibits tumor growth and liver and lung metastasis in EGFR T790M osimertinib- and trastuzumab-resistant and ERBB2-expressing NSCLC via the reduction of ERBB2 |
| title_full_unstemmed | Nanocage-incorporated engineered destabilized 3'UTR ARE of ERBB2 inhibits tumor growth and liver and lung metastasis in EGFR T790M osimertinib- and trastuzumab-resistant and ERBB2-expressing NSCLC via the reduction of ERBB2 |
| title_short | Nanocage-incorporated engineered destabilized 3'UTR ARE of ERBB2 inhibits tumor growth and liver and lung metastasis in EGFR T790M osimertinib- and trastuzumab-resistant and ERBB2-expressing NSCLC via the reduction of ERBB2 |
| title_sort | nanocage incorporated engineered destabilized 3 utr are of erbb2 inhibits tumor growth and liver and lung metastasis in egfr t790m osimertinib and trastuzumab resistant and erbb2 expressing nsclc via the reduction of erbb2 |
| topic | NSCLC EGFRT790M ERBB2/HER2 osimertinib and trastuzumab resistance engineered mRNA destabilization mRNA overwriting iron oxide nanocages (IO) |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2024.1344852/full |
| work_keys_str_mv | AT chidiebereuawah nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT chidiebereuawah nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT joosunmun nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT alokaparagodaarachchi nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT alokaparagodaarachchi nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT barisboylu nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT martinnzegwu nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT hiroshimatsui nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT hiroshimatsui nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT hiroshimatsui nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT hiroshimatsui nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT olorunseunogunwobi nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT olorunseunogunwobi nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 AT olorunseunogunwobi nanocageincorporatedengineereddestabilized3utrareoferbb2inhibitstumorgrowthandliverandlungmetastasisinegfrt790mosimertinibandtrastuzumabresistantanderbb2expressingnsclcviathereductionoferbb2 |