The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC
Abstract Mutation in KRAS protooncogene represents one of the most common genetic alterations in NSCLC and has posed a great therapeutic challenge over the past ~ 40 years since its discovery. However, the pioneer work from Shokat’s lab in 2013 has led to a recent wave of direct KRASG12C inhibitors...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-11-01
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| Series: | Experimental Hematology & Oncology |
| Online Access: | https://doi.org/10.1186/s40164-023-00453-8 |
| _version_ | 1797637042090278912 |
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| author | Firas Batrash Mahmoud Kutmah Jun Zhang |
| author_facet | Firas Batrash Mahmoud Kutmah Jun Zhang |
| author_sort | Firas Batrash |
| collection | DOAJ |
| description | Abstract Mutation in KRAS protooncogene represents one of the most common genetic alterations in NSCLC and has posed a great therapeutic challenge over the past ~ 40 years since its discovery. However, the pioneer work from Shokat’s lab in 2013 has led to a recent wave of direct KRASG12C inhibitors that utilize the switch II pocket identified. Notably, two of the inhibitors have recently received US FDA approval for their use in the treatment of KRASG12C mutant NSCLC. Despite this success, there remains the challenge of combating the resistance that cell lines, xenografts, and patients have exhibited while treated with KRASG12C inhibitors. This review discusses the varying mechanisms of resistance that limit long-lasting effective treatment of those direct inhibitors and highlights several novel therapeutic approaches including a new class of KRASG12C (ON) inhibitors, combinational therapies across the same and different pathways, and combination with immunotherapy/chemotherapy as possible solutions to the pressing question of adaptive resistance. |
| first_indexed | 2024-03-11T12:43:42Z |
| format | Article |
| id | doaj.art-5cab63bb0c0d4c29bd9307d421449ce4 |
| institution | Directory Open Access Journal |
| issn | 2162-3619 |
| language | English |
| last_indexed | 2024-03-11T12:43:42Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj.art-5cab63bb0c0d4c29bd9307d421449ce42023-11-05T12:09:44ZengBMCExperimental Hematology & Oncology2162-36192023-11-0112111910.1186/s40164-023-00453-8The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLCFiras Batrash0Mahmoud Kutmah1Jun Zhang2School of Medicine, University of Missouri Kansas CitySchool of Medicine, University of Missouri Kansas CityDivision of Medical Oncology, Department of Internal Medicine, University of Kansas Medical CenterAbstract Mutation in KRAS protooncogene represents one of the most common genetic alterations in NSCLC and has posed a great therapeutic challenge over the past ~ 40 years since its discovery. However, the pioneer work from Shokat’s lab in 2013 has led to a recent wave of direct KRASG12C inhibitors that utilize the switch II pocket identified. Notably, two of the inhibitors have recently received US FDA approval for their use in the treatment of KRASG12C mutant NSCLC. Despite this success, there remains the challenge of combating the resistance that cell lines, xenografts, and patients have exhibited while treated with KRASG12C inhibitors. This review discusses the varying mechanisms of resistance that limit long-lasting effective treatment of those direct inhibitors and highlights several novel therapeutic approaches including a new class of KRASG12C (ON) inhibitors, combinational therapies across the same and different pathways, and combination with immunotherapy/chemotherapy as possible solutions to the pressing question of adaptive resistance.https://doi.org/10.1186/s40164-023-00453-8 |
| spellingShingle | Firas Batrash Mahmoud Kutmah Jun Zhang The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC Experimental Hematology & Oncology |
| title | The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC |
| title_full | The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC |
| title_fullStr | The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC |
| title_full_unstemmed | The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC |
| title_short | The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC |
| title_sort | current landscape of using direct inhibitors to target krasg12c mutated nsclc |
| url | https://doi.org/10.1186/s40164-023-00453-8 |
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