▎ WuXi AppTec content team editor
In 1982, three laboratories discovered the first confirmed human oncogene RAS and cloned three variants: KRAS, HRAS, and NRAS. KRAS is the most commonly mutated oncogene, occurring in about a quarter of human tumors. While it's one of the most attractive targets for treating cancer, it took more than three decades of research by scientists to turn it into a protein that can be targeted. In May last year, Amgen's KRAS G12C inhibitor Lumakras received accelerated approval from the US FDA, marking a major breakthrough in breaking the "non-druggable" nature of KRAS.
Following the discovery of KRAS G12C inhibitors, scientists have turned their sights to other KRAS mutants and to develop pan-KRAS-targeted therapies that target many, if not all, OF KRAS mutants. Pan-KRAS targeted therapies have the potential to treat a wide range of patient populations, including cancers carrying KRASG12D, G12V, G13D, G12R, G12A mutations, as well as KRAS wild-type amplified cancers, and cancers that develop resistance to KRAS G12C inhibitors. A review recently published in Cancer Discovery provides an inventory of strategies for developing mutant-specific and broad-spectrum KRAS inhibitors and their application prospects. In today's article, WuXi AppTec's content team will share the wonderful content of this review with readers, click "Read more" at the end of the article to read the full review.
Broad prospects for targeting KRAS
KRAS mutations and wild-type KRAS amplification are common in patients with colorectal cancer (~45% in the US, ~49% in China), pancreatic cancer (~90% in the US, ~87% in China), and non-small cell lung cancer (NSCLC, ~35% in the US, ~13% in China). Among them, KRASG12C is the most common KRAS mutation in NSCLC patients, while KRASG12D and KRASG12V are the most common mutations in colorectal and pancreatic cancers.
Although KRAS mutations represent the most common genetic mutations in many cancer types, wild-type KRAS expands to the predominant type of other cancers (e.g., invasive ductal carcinoma of the breast, adenocarcinoma of the stomach, and cancer of the esophagus and gastroesophageal junction). A small percentage of patients carry multiple KRAS variants.
Proportion of different KRAS mutations among newly diagnosed cancer patients in the United States (Image source: Reference[1])
The review authors' analysis notes that approximately 11.6 percent of patients with newly diagnosed cancer in the United States in 2020 are likely to benefit from KRAS-targeted therapy. This patient population is close to the sum of patients who can benefit from all other FDA-approved targeted therapies, demonstrating the significant impact of targeted KRAS on improving patient outcomes. It is worth mentioning that the patient population benefiting from KRAS G12C inhibitors is only a small part of the population carrying the KRAS variant. Patients still need therapies that target other KRAS variants. The review authors argue that there are two strategies for targeting other KRAS variants, one is to develop mutant-specific KRAS inhibitors, and the other is to develop pan-KRAS inhibitors or protein degradation therapies.
Mutant-specific KRAS inhibitors
The success of KRAS G12C inhibitors has led to a proof of concept for the development of mutant-specific KRAS inhibitors. Amgen's sotoorasib and Mirati's adagrasib have shown promising anti-cancer activity in clinical trials by combining with KRAS in an inactive state and locking it in an inactive state. Currently, most KRAS G12C inhibitors target the inactive state of KRAS.
▲Some mutant-specific KRAS inhibitors in research (Image source: Reference[1])
The difference is the RMC-6291 developed by Revolution Medicines. The macrocyclic molecule acts like a molecular glue, bonding KRAS G12C and cyclophilin A together to form a ternary complex that blocks the active KRAS G12C from binding to the RAS effector protein, thereby inhibiting downstream signaling. A preclinical study published in this year's AACR showed that this KRAS G12C inhibitor exhibited stronger anti-cancer activity in mouse NSCLC models than inhibitors targeting the inactive state KRAS G12C mutant.
▲ Revolution Medicines' ternary complex platform can selectively target the KRAS G12C of the activation state (Image source: Revolution Medicines official website)
Beyond targeting KRAS G12C, the next frontier is the development of effective therapies that target all other KRAS mutants. Since cysteine in the KRAS G12C mutation covalently bound to the drug is absent in other KRAS mutants, strategies for developing covalent KRAS G12C inhibitors may not necessarily be used to target other KRAS mutants. Non-covalent inhibitors may have better prospects in this regard. Mirati and Boehringer Ingelheim presented inhibitors at scientific conferences that can bind to KRAS G12D reversibility. Mirati's MRTX1133, and Boehringer Ingelheim's BI-KRASG12D2 and BI-KRASG12D3 have shown activity in KRAS G12D-driven tumor transplant models.
Revolution Medicines used its ternary complex platform to develop a covalent KRAS G12D inhibitor that targets activated states. It selectively binds to aspartic acid of the KRAS G12D mutant, effectively inhibits signaling pathway conduction, and does not affect wild-type KRAS. In the pancreatic cancer transplant model, it drives tumors carrying KRASG12D mutations to shrink and exhibit good tolerance.
Image credit: Revolution Medicines
Covalent inhibitors of the company targeting active KRAS G13C mutants have also shown anti-cancer activity in preclinical trials.
Development strategies for pan-KRAS targeted therapies
The development of pan-KRAS inhibitors capable of inhibiting the activity of all KRAS mutants has the potential to treat patients with widely borne KRAS mutant cancer, and in this regard, the development strategy can be subdivided into indirect inhibition and direct inhibition.
Indirect suppression policies
The main targets that indirectly inhibit KRAS activity include SHP2 and SOS1. The theoretical basis for these targets is the scientific study that found that multiple carcinogenic KRAS mutant proteins (including KRAS G12C) still transition between inactivation and activation states, and rely on upstream activation to exert their full carcinogenicity.
SHP2 inhibitors are able to disrupt SOS1-mediated GTP-substituted GDP bound to KRAS, thereby inhibiting KRAS activation. Moreover, SHP2 inhibitors may also modulate T cells and macrophages to stimulate an anti-tumor immune response. At least nine SHP2 inhibitors have been tested in clinical trials. Among them, RMC-4630 from Revolution Medicines, TNO155 from Novartis and JAB-3068 from AbbVie have entered Phase 2 clinical development.
▲Some SHP2 inhibitors under research (Image source: Reference[1])
SOS1 inhibitors block guanine nucleotide exchange factor (GEF) SOS1 protein from binding to the inactive KRAS, preventing GTP from replacing GDP, thereby inhibiting KRAS activity. Boehringer Ingelheim's BI 1701963 was the first SOS1 inhibitor to enter clinical trials. Preliminary clinical trial results show that BI 1701963 showed good tolerability as monotherapy, with 7 of the 31 patients carrying KRAS mutations stable. The main purpose of this trial is to measure the tolerability of BI 1701963 and to confirm the recommended dose in a phase 2 clinical trial of combination therapy. Revolution Medicines (RMC-5845), Schr dinger (SDGR5), Genhouse Bio (GH52), Erasca (ERAS-9), and Mirati Therapeutics' SOS1 inhibitors are all in the preclinical phase.
▲Some SOS1 inhibitors under research (Image source: References[1])
Since both SOS1 inhibitors and SHP2 inhibitors allow KRAS to be inactivated in binding to GDP for more time, there is a good scientific basis for their use in combination with mutant-specific inhibitors that bind to inactivated KRAS (such as KRAS G12C inhibitors). Preclinical studies have also shown that shp2 inhibitor/KRAS G12C inhibitor combination, as well as SOS1 inhibitor/KRAS G12C inhibitor combination, have shown synergistic effects and enhanced anti-cancer effects. Currently, these combinations are being tested in clinical trials.
Direct suppression policy
Using KRAS fragment screening and structure-based drug design, Boehringer Ingelheim reported the discovery of pan-KRAS inhibitors acting directly on KRAS, and pan-KRAS protein degraders. In a variety of KRAS-driven cell lines, pan-KRAS inhibitors exhibit activity, and cell lines carrying HRAS and NRAS mutations are not sensitive to it. Importantly, this pan-KRAS inhibitor also exhibited activity against a range of cell lines carrying KRAS amplification without affecting cells with normal KRAS copy numbers.
Protein degraders represented by PROTAC can use the protein degradation mechanism of cells to target the degradation of specific proteins. This emerging mode of treatment may provide a means of degrading all KRAS mutants.
At present, scientists have successfully converted covalent inhibitors targeting KRAS G12C into PROTAC molecules, but protaC molecules covalently bound to the target have also been consumed in the process of degrading KRAS, so the advantages compared with covalent KRAS G12C inhibitors are not clear.
Boehringer Ingelheim has reported generating a PROTAC protein degrader that selectively degrades KRAS, which is capable of degrading all common KRAS mutants without affecting NRAS and HRAS. Theoretically, PROTAC protein degraders have the potential to block the KRAS signaling pathway more quickly and durably. Moreover, by selecting the appropriate E3 ligase, the PROTAC molecule may acquire tissue selectivity. However, whether this mode of action can better prevent the emergence of drug resistance still needs to be tested experimentally, because PROTAC molecules need to face different resistance generation mechanisms associated with the protein degradation process.
▲Some pan-KRAS inhibitors under research (Image source: Reference[1])
Comparison of pan-KRAS targeted therapy and KRAS mutant-specific targeted therapy
The authors of the article state that KRAS mutant-specific drugs and pan-KRAS drugs have different advantages and disadvantages.
KRAS mutant-specific drugs have a variety of advantages, first of all, they are expected to have deep and long-lasting target inhibition in clearly defined patient populations, and they have a lower risk of toxic side effects due to inhibition of wild-type KRAS and a higher likelihood of combining with other drugs. In future clinical research and practice, such drugs are an obvious choice in early treatment settings, whether as monotherapy or in combination with other targeted and immunotherapies. However, the ability to find inhibitors that target other KRAS mutants beyond KRAS G12C and KRAS G12D still requires experimental verification. Recently, at the AACR conference, Dr. Kevan M. Shokat's team at the University of California, San Francisco, revealed compounds that can target KRAS G12S mutations, showing the prospect of targeting other KRAS mutants.
Pan-KRAS drugs face tolerability issues due to inhibition of wild-type KRAS function. Experiments in mice showed that knockout KRAS, while not immediately toxic, reduced the survival rate of animals when they reached 8 months of age. The consequences of inhibiting or degrading wild-type KRAS in normal tissues in humans still need to be clarified.
The advantage of pan-KRAS drugs is that they can treat a wide range of patient populations, especially those who do not benefit from existing KRAS mutant-specific inhibitors. Pan-KRAS drugs are the first choice for the treatment of wild-type KRAS-driven cancers, which include amplification of the wild-type KRAS gene, as well as cancers driven by the loss of the tumor suppressor gene NF1, and neurofibromatosis type 1 and related cancers.
Pan-KRAS drugs may be more beneficial in treating patients with multiple KRAS mutations, or overcoming acquired resistance developed by patients through mutations in the KRAS protein.
Characteristics of mutant-specific KRAS drugs and pan-KRAS drugs (Image source: References[1])
Looking to the future
The authors say exciting scientific advances have emerged, both in mutant-specific KRAS inhibitors and in pan-KRAS inhibitors and degraders. A chapter on targeting mutants other than KRAS G12C is being written. They believe that these two types of KRAS drugs have highly complementary therapeutic concepts, and the combined use is expected to overcome all cancers that carry KRAS mutations.
Resources:
[1] Hofmann et al., (2022). Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants. Cancer Discovery, doi: 10.1158/2159-8290.CD-21-1331
[2] RMC-6291, a Next-Generation Tri-Complex KRASG12C(ON) Inhibitor, Outperforms KRASG12C(OFF) Inhibitors in Preclinical Models of KRASG12C Cancers. Retrieved April 21, 2022, from https://s3.us-west-2.amazonaws.com/rvmdpubs.revmed.com/2022/AACR_2022_Nichols.pdf
[3] RMC-9805 (RM-036), a First-in-Class, Orally-Bioavailable, Tri- Complex Covalent KRASG12D(ON) Inhibitor, Drives Profound Anti- Tumor Activity in KRASG12D Mutant Tumor Models. Retrieved April 21, 2022, from https://s3.us-west-2.amazonaws.com/rvmdpubs.revmed.com/2022/AACR_2022_Knox.pdf
[4] Special symposium commemorates 40th anniversary of KRAS discovery. Retrieved April 21, 2022, from https://www.aacrmeetingnews.org/news/special-symposium-commemorates-40th-anniversary-of-kras-discovery/?utm_source=twitter&utm_medium=social&utm_campaign=AACR-2022-Post1-assoc-twitter-share&utm_content=link-share&sf163723308=1
[5] Herdeis et al., (2021). Stopping the beating heart of Cancer: KRAS reviewed. Current Opinion in Structural Biology, https://doi.org/10.1016/j.sbi.2021.06.013
[6] Liu et al., (2019). Targeting the untargetable KRAS in cancer therapy. Acta Pharmaceutica Sinica B, https://doi.org/10.1016/j.apsb.2019.03.002
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