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RAS is one of the most common oncogenes in cancer patients, and currently includes three subtypes: KRAS, NRAS and HRAS.
Among them, NRAS mutations are more common in melanoma and acute myeloid leukemia, HRAS mutations are more common in bladder cancer and head and neck cancer, and KRAS mutations are more common than the other two, and most commonly occur in lung cancer, pancreatic cancer, and colorectal cancer.
This is a hot spot that scientists are striving to conquer.
RAS was once called a "non-drugable target" by the medical community.
Scientists have been exploring effective RAS inhibitors for more than 30 years, and it is only in recent years that major breakthroughs have been achieved.
Recently, the Nature sub-journal published the key advances in RAS-targeted therapies in the form of a poster titled RAS-targeted therapies, and sorted out and inventoried the development of drugs for RAS targets.
https://doi.
org/10.
1038/s41573-021-00220-6 Overview of RAS gene mutations At present, RAS inhibitors have developed a variety of therapies to prevent RAS mutations through direct or indirect methods.
This article will make a detailed inventory based on Nature’s review.
1.
Direct targeted therapy In recent years, direct targeted RAS therapy represented by KRAS G12C inhibitors has made significant progress.
KRAS gene mutations are mainly concentrated at codons 12, 13 and 61, of which codon 12 mutations account for more than 80%, including G12A, G12C, G12D, G12R, G12S and G12V, while KRAS G12C mutations account for more than 80% 12% of all KRAS mutations, and predominantly in non-small cell lung cancer (NSCLC).
KRAS G12C inhibitors can covalently bind to KRAS with G12C mutations and lock KRAS G12C mutants in an inactive state.
This therapy first achieved a major breakthrough in Amgen's AMG 510 inhibitor.
AMG 510 is mainly targeted at NSCLC.
It has been granted breakthrough therapy designation by the FDA at the end of 2020, and has obtained priority review and accelerated approval qualifications.
It has now entered Phase III clinical trial.
Another breakthrough in this field is Mirati.
Its inhibitor MRTX849 can "lock" KRAS G12C mutants in an inactive state by irreversibly binding them to the inactive state, thereby inhibiting the KRAS signaling pathway.
MRTX849 has shown promising anti-cancer activity in both phase I/II clinical trials and has entered the phase III clinical trials.
2.
Indirect targeted therapy The RAS gene has a very strong ability to bind to GTP or GDP.
However, when the receptor tyrosine kinase is activated, RAS will switch from an inactive state combined with GDP to an activated state combined with GTP , So as to continuously activate the downstream signal pathway targets such as RAF, MEK and ERK, so that cells continue to proliferate, differentiate, and form tumors.
Therefore, indirect targeted therapy usually prevents the activation of RAS and GTP binding by inhibiting the target in its signaling pathway.
This article will introduce several types of popular therapies.
1.
The EGFR inhibitor RAS gene is located in the downstream pathway of EGFR.
Its activation will activate the EGFR signaling pathway.
In this process, receptor tyrosine kinase will play a key role in promoting tumor cell proliferation and tumor blood vessel growth.
Generation and transfer.
Therefore, EGFR inhibitors will inhibit the activation of EGFR receptor tyrosine kinases and block the transduction of downstream signals, thereby reducing the mutational activation of RAS.
2.
Targeted blocking of RAS activation Taking KRAS as an example, the transition between inactivated and activated states of KRAS is regulated by two types of factors. One type is GTPase activating protein (GAP), which promotes the hydrolysis of GTP bound to KRAS into GDP, thereby inhibiting the activity of KRAS and leaving KRAS in an inactive state; the other is guanine nucleotide exchange factor (GEF).
), including SOS protein and SHP2 protein, these proteins catalyze the binding of KRAS and GTP, thereby promoting the activation of KRAS mutations.
Therefore, GEF inhibitors that target to block RAS activation have become the focus of inhibiting KRAS mutations.
At present, inhibiting GEF is mainly to develop SOS inhibitors and SHP2 inhibitors.
● SOS inhibitors mainly interfere with RAS-SOS1 interaction to block RAS activation.
BI-1701963 in Boehringer Ingelheim's R&D pipeline is an SOS1 inhibitor, which binds to the catalytic region of SOS1 to block the feedback driven by SOS1 and reduce the formation of KRAS activation.
The advantage of this inhibitor is that by selectively inhibiting SOS1, it can block the activity of a variety of KRAS mutants regardless of the type of KRAS mutation.
● SHP2 inhibitors have also attracted much attention.
SHP2 is a protein tyrosine phosphatase that participates in a variety of cancer-causing signal cascades.
It can directly dephosphorylate RAS, thereby enhancing its binding to the effector protein RAF and activates it.
Downstream MEK/ERK signaling pathway.
Targeted inhibition of SHP2 can not only slow down the growth of cancer cells, but also regulate immune function to activate its anti-tumor effect.
Novartis' TNO-155, JAB-3068 jointly developed by Jacos and AbbVie, and RMC-4630 jointly developed by Sanofi and Revolution are all betting on the SHP2 inhibitor track and have entered phase I clinical trials.
3.
After RAS that inhibits the inactivation of downstream signaling pathways is activated, multiple downstream signaling pathways can be activated, including MAPK signaling pathway, PI3K signaling pathway, and Ral-GEFs signaling pathway.
These signaling pathways are accelerating tumor cell survival and proliferation.
The role of this aspect cannot be underestimated. At the same time, because it is difficult to develop and design inhibitors that directly target RAS, scientists have focused their attention on the downstream signaling pathways.
At present, the most concentrated research is the MAPK pathway (RAF-MEK-ERK) and the PI3K pathway (p110- AKT-mTOR).
In the MAPK pathway, the abnormal function of any one of the RAF, MEK and ERK proteins can lead to serious tumor diseases.
RAF kinases include ARAF, BRAF and CRAF.
BRAF, as an important member of the RAF-MEK-ERK signal transduction pathway, mediates the combination of RAS and MAPK, and regulates tumor cell proliferation, differentiation and apoptosis.
When the BRAF gene undergoes carcinogenic changes and is activated, it will continue to phosphorylate MEK and downstream ERK, thereby promoting the growth, proliferation and survival of tumor cells.
● Currently, the inhibitors against RAF include Belvarafenib, LXH254, Lifirafenib, etc.
Among them, LXH254 is a new type of RAF inhibitor that can inhibit BRAF and CRAF dimers and BRAF monomers, but cannot inhibit ARAF.
It is mainly used in advanced solid tumors.
● Studies have shown that MEK inhibitors have significant effects on malignant tumors caused by both KRAS and BRAF mutations, especially in tumor cell lines with BRAF mutations (V600E), the negative feedback mechanism of the MEK pathway does not exist, making this type of tumors The sensitivity of the strain to MEK inhibitors is greatly increased.
At present, Roche's Cobimetinib, Novartis' Trametinib and Array's Binimetinib are all MEK inhibitors.
Among them, the combination of Array's Encorafenib and Binimetinib has been used to treat metastatic melanoma.
● ERK kinase is the only downstream target of MEK.
Inhibitors targeting the ERK target can effectively block the RAS-RAF-MEK-ERK signaling pathway and effectively reverse the resistance caused by the upstream BRAF and MEK mutations. Ulixertinib and LY3214996 are both ERK inhibitors.
Among them, Ulixertinib has entered phase I clinical trials as an ERK1/2 kinase inhibitor.
It has shown preclinical anticancer activity in BRAF mutant and RAS mutant cell lines.
In addition, domestic Hengrui Pharmaceuticals, Betta Pharmaceuticals, and Deqi Pharmaceuticals have also announced clinical trials of ERK inhibitors.
The PI3K signaling pathway plays an important role in complementing the MAPK signaling pathway.
The resistance of tumor cells to MAPK inhibitors to a large extent comes from the activation of the PI3K signaling pathway.
For the PI3K signaling pathway, Bayer's Copanlisib was approved by the U.
S.
FDA on September 14, 2017 for the treatment of recurrent follicular lymphoma, and was included in the list of breakthrough treatments by CDE at the end of 2020, and has been declared in China Listed.
Nature's reorganization of single-drug RAS-targeted drugs Nature's reorganization of RAS-targeted drug combinations In addition to the above therapies, there are also many therapies for RAS mutations, such as siRNA therapy, adoptive cell therapy, and tumor vaccines, waiting for clinical research and verification.
With the breakthrough of RAS's "non-medicability", let us look forward to more new developments in this field! End reference materials: [1] ]https://zhuanlan.
zhihu.
com/p/32612567
Among them, NRAS mutations are more common in melanoma and acute myeloid leukemia, HRAS mutations are more common in bladder cancer and head and neck cancer, and KRAS mutations are more common than the other two, and most commonly occur in lung cancer, pancreatic cancer, and colorectal cancer.
This is a hot spot that scientists are striving to conquer.
RAS was once called a "non-drugable target" by the medical community.
Scientists have been exploring effective RAS inhibitors for more than 30 years, and it is only in recent years that major breakthroughs have been achieved.
Recently, the Nature sub-journal published the key advances in RAS-targeted therapies in the form of a poster titled RAS-targeted therapies, and sorted out and inventoried the development of drugs for RAS targets.
https://doi.
org/10.
1038/s41573-021-00220-6 Overview of RAS gene mutations At present, RAS inhibitors have developed a variety of therapies to prevent RAS mutations through direct or indirect methods.
This article will make a detailed inventory based on Nature’s review.
1.
Direct targeted therapy In recent years, direct targeted RAS therapy represented by KRAS G12C inhibitors has made significant progress.
KRAS gene mutations are mainly concentrated at codons 12, 13 and 61, of which codon 12 mutations account for more than 80%, including G12A, G12C, G12D, G12R, G12S and G12V, while KRAS G12C mutations account for more than 80% 12% of all KRAS mutations, and predominantly in non-small cell lung cancer (NSCLC).
KRAS G12C inhibitors can covalently bind to KRAS with G12C mutations and lock KRAS G12C mutants in an inactive state.
This therapy first achieved a major breakthrough in Amgen's AMG 510 inhibitor.
AMG 510 is mainly targeted at NSCLC.
It has been granted breakthrough therapy designation by the FDA at the end of 2020, and has obtained priority review and accelerated approval qualifications.
It has now entered Phase III clinical trial.
Another breakthrough in this field is Mirati.
Its inhibitor MRTX849 can "lock" KRAS G12C mutants in an inactive state by irreversibly binding them to the inactive state, thereby inhibiting the KRAS signaling pathway.
MRTX849 has shown promising anti-cancer activity in both phase I/II clinical trials and has entered the phase III clinical trials.
2.
Indirect targeted therapy The RAS gene has a very strong ability to bind to GTP or GDP.
However, when the receptor tyrosine kinase is activated, RAS will switch from an inactive state combined with GDP to an activated state combined with GTP , So as to continuously activate the downstream signal pathway targets such as RAF, MEK and ERK, so that cells continue to proliferate, differentiate, and form tumors.
Therefore, indirect targeted therapy usually prevents the activation of RAS and GTP binding by inhibiting the target in its signaling pathway.
This article will introduce several types of popular therapies.
1.
The EGFR inhibitor RAS gene is located in the downstream pathway of EGFR.
Its activation will activate the EGFR signaling pathway.
In this process, receptor tyrosine kinase will play a key role in promoting tumor cell proliferation and tumor blood vessel growth.
Generation and transfer.
Therefore, EGFR inhibitors will inhibit the activation of EGFR receptor tyrosine kinases and block the transduction of downstream signals, thereby reducing the mutational activation of RAS.
2.
Targeted blocking of RAS activation Taking KRAS as an example, the transition between inactivated and activated states of KRAS is regulated by two types of factors. One type is GTPase activating protein (GAP), which promotes the hydrolysis of GTP bound to KRAS into GDP, thereby inhibiting the activity of KRAS and leaving KRAS in an inactive state; the other is guanine nucleotide exchange factor (GEF).
), including SOS protein and SHP2 protein, these proteins catalyze the binding of KRAS and GTP, thereby promoting the activation of KRAS mutations.
Therefore, GEF inhibitors that target to block RAS activation have become the focus of inhibiting KRAS mutations.
At present, inhibiting GEF is mainly to develop SOS inhibitors and SHP2 inhibitors.
● SOS inhibitors mainly interfere with RAS-SOS1 interaction to block RAS activation.
BI-1701963 in Boehringer Ingelheim's R&D pipeline is an SOS1 inhibitor, which binds to the catalytic region of SOS1 to block the feedback driven by SOS1 and reduce the formation of KRAS activation.
The advantage of this inhibitor is that by selectively inhibiting SOS1, it can block the activity of a variety of KRAS mutants regardless of the type of KRAS mutation.
● SHP2 inhibitors have also attracted much attention.
SHP2 is a protein tyrosine phosphatase that participates in a variety of cancer-causing signal cascades.
It can directly dephosphorylate RAS, thereby enhancing its binding to the effector protein RAF and activates it.
Downstream MEK/ERK signaling pathway.
Targeted inhibition of SHP2 can not only slow down the growth of cancer cells, but also regulate immune function to activate its anti-tumor effect.
Novartis' TNO-155, JAB-3068 jointly developed by Jacos and AbbVie, and RMC-4630 jointly developed by Sanofi and Revolution are all betting on the SHP2 inhibitor track and have entered phase I clinical trials.
3.
After RAS that inhibits the inactivation of downstream signaling pathways is activated, multiple downstream signaling pathways can be activated, including MAPK signaling pathway, PI3K signaling pathway, and Ral-GEFs signaling pathway.
These signaling pathways are accelerating tumor cell survival and proliferation.
The role of this aspect cannot be underestimated. At the same time, because it is difficult to develop and design inhibitors that directly target RAS, scientists have focused their attention on the downstream signaling pathways.
At present, the most concentrated research is the MAPK pathway (RAF-MEK-ERK) and the PI3K pathway (p110- AKT-mTOR).
In the MAPK pathway, the abnormal function of any one of the RAF, MEK and ERK proteins can lead to serious tumor diseases.
RAF kinases include ARAF, BRAF and CRAF.
BRAF, as an important member of the RAF-MEK-ERK signal transduction pathway, mediates the combination of RAS and MAPK, and regulates tumor cell proliferation, differentiation and apoptosis.
When the BRAF gene undergoes carcinogenic changes and is activated, it will continue to phosphorylate MEK and downstream ERK, thereby promoting the growth, proliferation and survival of tumor cells.
● Currently, the inhibitors against RAF include Belvarafenib, LXH254, Lifirafenib, etc.
Among them, LXH254 is a new type of RAF inhibitor that can inhibit BRAF and CRAF dimers and BRAF monomers, but cannot inhibit ARAF.
It is mainly used in advanced solid tumors.
● Studies have shown that MEK inhibitors have significant effects on malignant tumors caused by both KRAS and BRAF mutations, especially in tumor cell lines with BRAF mutations (V600E), the negative feedback mechanism of the MEK pathway does not exist, making this type of tumors The sensitivity of the strain to MEK inhibitors is greatly increased.
At present, Roche's Cobimetinib, Novartis' Trametinib and Array's Binimetinib are all MEK inhibitors.
Among them, the combination of Array's Encorafenib and Binimetinib has been used to treat metastatic melanoma.
● ERK kinase is the only downstream target of MEK.
Inhibitors targeting the ERK target can effectively block the RAS-RAF-MEK-ERK signaling pathway and effectively reverse the resistance caused by the upstream BRAF and MEK mutations. Ulixertinib and LY3214996 are both ERK inhibitors.
Among them, Ulixertinib has entered phase I clinical trials as an ERK1/2 kinase inhibitor.
It has shown preclinical anticancer activity in BRAF mutant and RAS mutant cell lines.
In addition, domestic Hengrui Pharmaceuticals, Betta Pharmaceuticals, and Deqi Pharmaceuticals have also announced clinical trials of ERK inhibitors.
The PI3K signaling pathway plays an important role in complementing the MAPK signaling pathway.
The resistance of tumor cells to MAPK inhibitors to a large extent comes from the activation of the PI3K signaling pathway.
For the PI3K signaling pathway, Bayer's Copanlisib was approved by the U.
S.
FDA on September 14, 2017 for the treatment of recurrent follicular lymphoma, and was included in the list of breakthrough treatments by CDE at the end of 2020, and has been declared in China Listed.
Nature's reorganization of single-drug RAS-targeted drugs Nature's reorganization of RAS-targeted drug combinations In addition to the above therapies, there are also many therapies for RAS mutations, such as siRNA therapy, adoptive cell therapy, and tumor vaccines, waiting for clinical research and verification.
With the breakthrough of RAS's "non-medicability", let us look forward to more new developments in this field! End reference materials: [1] ]https://zhuanlan.
zhihu.
com/p/32612567
