Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges
Abstract Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable dr...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-10-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12943-021-01422-7 |
| _version_ | 1819124295086899200 |
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| author | Daolin Tang Guido Kroemer Rui Kang |
| author_facet | Daolin Tang Guido Kroemer Rui Kang |
| author_sort | Daolin Tang |
| collection | DOAJ |
| description | Abstract Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade. |
| first_indexed | 2024-12-22T07:21:58Z |
| format | Article |
| id | doaj.art-24ac5b8515ee48ada5b687fdb43084a7 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-22T07:21:58Z |
| publishDate | 2021-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-24ac5b8515ee48ada5b687fdb43084a72022-12-21T18:34:14ZengBMCMolecular Cancer1476-45982021-10-0120112410.1186/s12943-021-01422-7Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challengesDaolin Tang0Guido Kroemer1Rui Kang2The Third Affiliated Hospital, Guangzhou Medical UniversityCentre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de FranceDepartment of Surgery, UT Southwestern Medical CenterAbstract Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.https://doi.org/10.1186/s12943-021-01422-7Gene mutationCovalent inhibitorDrug resistanceKRASTargeted therapy |
| spellingShingle | Daolin Tang Guido Kroemer Rui Kang Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges Molecular Cancer Gene mutation Covalent inhibitor Drug resistance KRAS Targeted therapy |
| title | Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges |
| title_full | Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges |
| title_fullStr | Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges |
| title_full_unstemmed | Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges |
| title_short | Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges |
| title_sort | oncogenic kras blockade therapy renewed enthusiasm and persistent challenges |
| topic | Gene mutation Covalent inhibitor Drug resistance KRAS Targeted therapy |
| url | https://doi.org/10.1186/s12943-021-01422-7 |
| work_keys_str_mv | AT daolintang oncogenickrasblockadetherapyrenewedenthusiasmandpersistentchallenges AT guidokroemer oncogenickrasblockadetherapyrenewedenthusiasmandpersistentchallenges AT ruikang oncogenickrasblockadetherapyrenewedenthusiasmandpersistentchallenges |