RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumors
The mutation of K‐RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K‐RAS mutations. The reduced sensitivity of K‐RAS‐mutated cells to certain MEK inhibitors...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-08-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12698 |
| _version_ | 1811293163293245440 |
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| author | Xi Yuan Zhiyu Tang Rong Du Zhan Yao Shing‐Hu Cheung Xinwen Zhang Jing Wei Yuan Zhao Yunguang Du Ye Liu Xiaoxia Hu Wenfeng Gong Yong Liu Yajuan Gao Zhiyue Huang Zongfu Cao Min Wei Changyou Zhou Lai Wang Neal Rosen Paul D. Smith Lusong Luo |
| author_facet | Xi Yuan Zhiyu Tang Rong Du Zhan Yao Shing‐Hu Cheung Xinwen Zhang Jing Wei Yuan Zhao Yunguang Du Ye Liu Xiaoxia Hu Wenfeng Gong Yong Liu Yajuan Gao Zhiyue Huang Zongfu Cao Min Wei Changyou Zhou Lai Wang Neal Rosen Paul D. Smith Lusong Luo |
| author_sort | Xi Yuan |
| collection | DOAJ |
| description | The mutation of K‐RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K‐RAS mutations. The reduced sensitivity of K‐RAS‐mutated cells to certain MEK inhibitors (MEKi) is associated with the feedback phosphorylation of MEK by C‐RAF and with the reactivation of mitogen‐activated protein kinase (MAPK) signaling. Here, we report that the RAF dimer inhibitors lifirafenib (BGB‐283) and compound C show a strong synergistic effect with MEKi, including mirdametinib (PD‐0325901) and selumetinib, in suppressing the proliferation of K‐RAS‐mutated non‐small‐cell lung cancer and colorectal cancer (CRC) cell lines. This synergistic effect was not observed with the B‐RAFV600E selective inhibitor vemurafenib. Our mechanistic analysis revealed that RAF dimer inhibition suppresses RAF‐dependent MEK reactivation and leads to the sustained inhibition of MAPK signaling in K‐RAS‐mutated cells. This synergistic effect was also observed in several K‐RAS mutant mouse xenograft models. A pharmacodynamic analysis supported a role for the synergistic phospho‐ERK blockade in enhancing the antitumor activity observed in the K‐RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K‐RAS‐mutated cancers, and have led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K‐RAS mutations and other MAPK pathway aberrations. |
| first_indexed | 2024-04-13T04:56:58Z |
| format | Article |
| id | doaj.art-3c9d127250f544f0b8e196531da074da |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-13T04:56:58Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-3c9d127250f544f0b8e196531da074da2022-12-22T03:01:27ZengWileyMolecular Oncology1574-78911878-02612020-08-011481833184910.1002/1878-0261.12698RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumorsXi Yuan0Zhiyu Tang1Rong Du2Zhan Yao3Shing‐Hu Cheung4Xinwen Zhang5Jing Wei6Yuan Zhao7Yunguang Du8Ye Liu9Xiaoxia Hu10Wenfeng Gong11Yong Liu12Yajuan Gao13Zhiyue Huang14Zongfu Cao15Min Wei16Changyou Zhou17Lai Wang18Neal Rosen19Paul D. Smith20Lusong Luo21Department of Discovery Biology BeiGene (Beijing) Co., Ltd. ChinaDepartment of Pharmacology BeiGene (Beijing) Co., Ltd. ChinaDepartment of Discovery Biology BeiGene (Beijing) Co., Ltd. ChinaProgram in Molecular Pharmacology Memorial Sloan Kettering Cancer Center New York NY USADepartment of Discovery Biology BeiGene (Beijing) Co., Ltd. ChinaDepartment of Discovery Biology BeiGene (Beijing) Co., Ltd. ChinaDepartment of Discovery Biology BeiGene (Beijing) Co., Ltd. ChinaDepartment of Discovery Biology BeiGene (Beijing) Co., Ltd. ChinaDepartment of Biochemistry BeiGene (Beijing) Co., Ltd. ChinaDepartment of Biochemistry BeiGene (Beijing) Co., Ltd. ChinaDepartment of Pharmacology BeiGene (Beijing) Co., Ltd. ChinaDepartment of Pharmacology BeiGene (Beijing) Co., Ltd. ChinaDepartment of Pharmacology BeiGene (Beijing) Co., Ltd. ChinaDepartment of Pharmacology BeiGene (Beijing) Co., Ltd. ChinaGlobal Statistics and Data Science BeiGene (Shanghai) Co., Ltd. ChinaDepartment of Pharmacology BeiGene (Beijing) Co., Ltd. ChinaDepartment of Biochemistry BeiGene (Beijing) Co., Ltd. ChinaDepartment of Chemistry BeiGene (Beijing) Co., Ltd. ChinaDepartment of Pharmacology BeiGene (Beijing) Co., Ltd. ChinaProgram in Molecular Pharmacology Memorial Sloan Kettering Cancer Center New York NY USAAstraZeneca CRUK Cambridge Institute Robinson Way UKExternal Innovation BeiGene, Ltd. San Mateo CA USAThe mutation of K‐RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K‐RAS mutations. The reduced sensitivity of K‐RAS‐mutated cells to certain MEK inhibitors (MEKi) is associated with the feedback phosphorylation of MEK by C‐RAF and with the reactivation of mitogen‐activated protein kinase (MAPK) signaling. Here, we report that the RAF dimer inhibitors lifirafenib (BGB‐283) and compound C show a strong synergistic effect with MEKi, including mirdametinib (PD‐0325901) and selumetinib, in suppressing the proliferation of K‐RAS‐mutated non‐small‐cell lung cancer and colorectal cancer (CRC) cell lines. This synergistic effect was not observed with the B‐RAFV600E selective inhibitor vemurafenib. Our mechanistic analysis revealed that RAF dimer inhibition suppresses RAF‐dependent MEK reactivation and leads to the sustained inhibition of MAPK signaling in K‐RAS‐mutated cells. This synergistic effect was also observed in several K‐RAS mutant mouse xenograft models. A pharmacodynamic analysis supported a role for the synergistic phospho‐ERK blockade in enhancing the antitumor activity observed in the K‐RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K‐RAS‐mutated cancers, and have led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K‐RAS mutations and other MAPK pathway aberrations.https://doi.org/10.1002/1878-0261.12698combination therapyMEK inhibitorRAF dimer inhibitorRAS‐mutated cancersynergy |
| spellingShingle | Xi Yuan Zhiyu Tang Rong Du Zhan Yao Shing‐Hu Cheung Xinwen Zhang Jing Wei Yuan Zhao Yunguang Du Ye Liu Xiaoxia Hu Wenfeng Gong Yong Liu Yajuan Gao Zhiyue Huang Zongfu Cao Min Wei Changyou Zhou Lai Wang Neal Rosen Paul D. Smith Lusong Luo RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumors Molecular Oncology combination therapy MEK inhibitor RAF dimer inhibitor RAS‐mutated cancer synergy |
| title | RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumors |
| title_full | RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumors |
| title_fullStr | RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumors |
| title_full_unstemmed | RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumors |
| title_short | RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumors |
| title_sort | raf dimer inhibition enhances the antitumor activity of mek inhibitors in k ras mutant tumors |
| topic | combination therapy MEK inhibitor RAF dimer inhibitor RAS‐mutated cancer synergy |
| url | https://doi.org/10.1002/1878-0261.12698 |
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