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KRAS G12D: The Next Frontier in Cancer Therapy

KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) has been deemed a challenging therapeutic target, even “undruggable”, after drug-targeting efforts over the past four decades. Recently, there have been surprising advances in directly targeted drugs for KRAS, especially in KRASG12C inhibitors, such as Sotorasib (AMG510), Adagrasib (MRTX849) and Fulzerasib (GFH925). However, their efficacy is somewhat limited compared to that of other targeted therapies owing to intrinsic resistance or early acquisition of resistance. While G12C is the predominant subtype of KRAS mutations in non-small-cell lung cancer (NSCLC), G12D is prevalent in colorectal and pancreatic cancers.
The 2025 AACR Annual Meeting, held from April 25 to 30 in Chicago, Illinois, USA, once again highlighted KRAS as a highly sought-after therapeutic target, with significant research advances driving the field forward. In this issue, we will explore the latest developments and challenges in KRAS-targeted therapies.
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KRAS Mutations and Cancer
SuccessfullyTargeting KRAS G12C
Advances in KRAS G12D Inhibitors
KRAS Mutations and Cancer
SuccessfullyTargeting KRAS G12C
Advances in KRAS G12D Inhibitors
KRAS Mutations and Cancer
KRAS mutations commonly occur in NSCLC, colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC)[1-2]. The KRAS activating mutations most commonly occur as single nucleotide substitutions in 4 hotspot codons – 12, 13, 61 and 146. Codon 12 is the most frequently mutation, with the G12D mutation generally the most prevalent, followed by G12V, G12C, and others[2-3]. The G12C mutation inhibits the binding between GAP and KRAS, thereby suppressing GTP hydrolysis and locking the G12C mutated KRAS in its active state. Active KRAS induces signal transduction via the MAPK and PI3K pathways, promoting cell proliferation, growth, and survival, thereby facilitating tumor development[1,4]. The KRAS G12V variant mutation is the second most prevalent oncogenic alteration in KRAS-driven cancers, inducing aberrant activation of the mitogen-activated protein kinase (MAPK) pathway and promoting tumorigenesis and metastasis.
Figure. 1. Frequency of RAS mutations in major cancer types[5].

A．Distribution of KRAS (green), HRAS (yellow), and NRAS (pink) mutation frequencies across the major cancer types. B. Most frequently mutated amino acids (>5%) in KRAS-mutated cancers: top, NSCLC; middle, PDAC; bottom, CRC.

KRAS is a GTPase that belongs to the Rat Sarcoma Viral Oncogene family (RAS), with the ability to hydrolyze GTP into GDP. Under normal physiological conditions, KRAS oscillates between an inactive GDP-bound state and an active GTP-bound state, transducing signals from outside the cell to the inside. Upon activation of receptor tyrosine kinases (RTKs), guanine nucleotide exchange factors (GEFs) bind with KRAS, facilitating the replacement of bound guanosine diphosphate (GDP) with GTP, switching KRAS to its active state[6]. Meanwhile, GAPs maintain KRAS in an inactive state by strengthening the bond between GDP and KRAS.
Figure. 2. RAS signaling pathway[5].

Receptor tyrosine kinases (RTKs) facilitate the activation of RAS proteins by promoting the exchange of GDP for GTP via GEFs, such as SOS1. Active RAS drives numerous pro-oncogenic pathways.

Successfully Targeting KRAS G12C
KRAS is small and has a considerably smooth and shallow surface, resulting in difficulty of small molecule binding to the KRAS. There is no other pocket on the surface of KRAS that can bind to small molecules except the GTP binding pocket, but targeting the GTP binding pocket is quite difficult[1]. Thus, KRAS has long been considered an 'undruggable' target. The discovery of the switch-II pocket has led to the development of specific KRASG12C inhibitors for clinical use. Among them, Sotorasib and Adagrasib were approved by the FDA in 2021 and 2022, respectively. Fulzerasib received its first approval in 2024 in China. All these drugs are used for the treatment of KRASG12C mutation-positive NSCLC.
Both Sotorasib and Adagrasib monotherapy exhibited significantly lower objective response rate (ORR) in CRC compared with NSCLC. Epidermal growth factor receptor (EGFR) activation was identified as a basis for the lower response in CRC, with additional EGFR inhibition together with BRAF inhibitor treatment overcoming this issue[7]. Combining Sotorasib with Panitumumab (a EGFR inhibitor) improved progression-free survival (PFS) to 5.6 months compared with 2.2 months for the group of KRASG12C mutated advanced CRC patients receiving trifluridine-tipiracil or regorafenib[8]. A similar improvement in ORR (30.2%) was observed with Adagrasib in combination with Cetuximab (a EGFR inhibitor)[9]. Based on these findings, the FDA granted accelerated approval in 2024 to this combination therapy for KRASG12C mutated CRC.
In addition, several pan-RAS inhibitors are currently being developed. Boehringer Ingelheim announced a SOS1 inhibitor, BI-1701963, that disrupts SOS1-mediated nucleotide exchange of KRAS. Besides, given an integral role played by SHP2 in KRAS activation, several SHP2 inhibitors, such as TNO155, RMC-4630, and JAB-3068, are now being tested in clinical trials[10].
Table 1. FDA-approved KRASG12C inhibitor clinical trials.
Phase Clinical trial number Drugs Cancer ORR(%) DCR(%) PFS
(months)		 OS
(months)		 Refs
I NCT03600883 Sotorasib NSCLC 32.0 88.1 6.3 N/A [11,17]
CRC N/A 73.8 4.0 N/A [17]
II NSCLC 37.1 80.6 6.8 12.5 [11]
I/II NCT04185883 Sotorasib + Panitumumab CRC 30.0 92.5 5.7 15.2 [12]
III NCT05198934 Sotorasib + Panitumumab CRC 30.2 71.7 5.6 N/A [8,13]
I/II NCT03785249 Adagrasib Solid tumor 35.1 86.0 7.4 14.0 [14]
Adagrasib NSCLC 42.9 86.0 6.5 12.6 [11,15]
Adagrasib PDAC 33.3 81.0 5.4 8.0 [14]
Adagrasib + Cetuximab CRC 46.0 100 6.9 13.4 [16]
I NCT04449874 Divarasib (GDC-6036) + Migoprotafib (GDC-1971) NSCLC 43.8 / 15.2 / [18]

Abbreviations: objective response rate (ORR); progression-free survival (PFS); disease control rate (DCR); overall survival (OS).

Advances in KRAS G12D Inhibitors
Due to the high prevalence of the other KRAS mutations, the development of other mutant-selective inhibitors as well as pan-KRAS inhibitors is ongoing and some of these novel KRAS inhibitors are being tested in clinical trials. In particular, KRASG12D has emerged as a key area of interest in the development of new inhibitors, since this mutation represents ~28% of all KRAS mutations and is the most prevalent mutation in both CRC and PDAC[5]. Currently, there are no FDA-approved KRASG12D selective inhibitors, and cancers with KRASG12D mutations represent a significant unmet medical need.
Figure. 3. Clinical stages of RAS inhibitors[5].
The KRASG12C inhibitors covalently bind to the cysteine residue in the KRASG12C mutant, stabilizing the protein in its inactive GDP-bound state. Unfortunately, this strategy does not apply to KRASG12D. Because Asp12 of KRASG12D has a carboxyl group, it is weaker nucleophilic than the sulfhydryl group of cysteine[2]. This difference results in compounds, such as MRTX849, with significant effects on KRASG12C, but not on KRASG12D.
Due to the inability to directly target KRASG12D, Mirati Therapeutics modified the structure of MRTX849 by replacing the acrylamide group with piperazine, enabling non-covalent binding through intermolecular ionic interactions. This led to the development of MRTX1133[2-3]. The piperazine group of MRTX1133 forms ionic bonds with aspartic acid to achieve non-covalent binding. The non-covalent binding of MRTX1133 to KRASG12D prevents nucleotide exchange and binding of effector RAF, thereby inhibiting the protein-protein interaction necessary for the activation of KRAS downstream pathways[2-3]. Since the overall design of MRTX-1133 was based on MRTX849, other cancer drugs targeting G12C can also be modified to be reactive against G12D-driven cancers.
Figure. 4. Structures of KRAS surfaces targeted by KRAS mutant inhibitors[2].

A. Switch-II pocket (purple) of KRAS (G12C) bound to AMG510. B. MRTX1133 with KRAS G12D/GDP.

The development strategy of Zoldonrasib (RMC-9805) is different from that of MRTX1133. RMC-9805 first forms a non-covalent bond between KRASG12D and cyclophilin-A, forming a tri-complex of KRAS, cyclophilin-A, and RMC-9805, which results in slow covalent binding of RMC-9805 to the mutated aspartic acid and blocks the irreversible downstream binding of KRAS effectors[3,8]. This interaction causes a selective and persistent modification of KRASG12D by disrupting the downstream KRASG12D signaling effectors (e.g., RAF kinases), thus inducing apoptosis and inhibiting cell proliferation.
Among the KRASG12D PDAC patients who received at least 14 weeks of RMC-9805 treatment, the ORR was 30% (n = 12), and the DCR was 80% (n = 32)[19]. Furthermore, RMC-9805 has demonstrated excellent safety characteristics and is generally well-tolerated across different dose. These results indicate that RMC-9805 has a promising initial clinical profile.
Figure. 5. Encouraging initial antitumor activity in PDAC patients treated with RMC-9805[19].
Both MRTX1133 and RMC-9805 only bind to KRASG12D in the active (ON; GTP-bound) state. In contrast, VS-7375 (GFH375) binds to KRASG12D in both the active and inactive (OFF; GDP-bound) states. Thus, VS-7375 has the potential to more completely inhibit KRASG12D signaling and tumor growth than compounds that block KRASG12D only in the OFF state or only in the ON state. VS-7375 has demonstrated a promising anti-tumor activity in multiple KRASG12D tumor models in vivo as single agent and in combination with other anticancer therapies including cetuximab[20]. These results support the ongoing clinical evaluation of VS-7375 for treatment of patients with KRASG12D mutant cancers.
Figure. 6. Mice bearing LS513 KRAS G12D-mutant colorectal cancer cells were treated with VS7375, RMC-9805 or RMC-6263 for 28 days[20].
Figure. 7. Mice bearing LS513, AsPC-1 or LU876 KRAS G12D-mutant tumors were treated with VS-7375 or Cetuximab[20].
There is also a KRASG12D degrader ASP3082, which binds KRASG12D to a E3 Ligase to degrade the protein[3]. Other KRASG12D inhibitors, including HRS-4642, TH-Z835, JAB-22000 and ERAS-4, are also in development.
Summary
Specific KRASG12C inhibitors have changed the therapeutic landscape of KRAS-driven tumors and have benefited many patients with KRAS-mutated cancers. Unfortunately, innate and acquired resistance to KRAS inhibitors has hindered their development, making these new drugs less effective or even ineffective. As one of the common KRAS mutations, KRASG12D drives a highly immunosuppressive tumor microenvironment and exhibits potent oncogenic potential. Therefore, the development of KRASG12D inhibitors and other pan-KRAS inhibitors is a new direction for KRAS targeted therapy.
MedChemExpress—Master of active small molecules
MCE provides abundant KRAS, SOS1, SHP2 or other related-target inhibitors for you.
Cat. No. Name Active Indications Targets
Act to directly inhibit KRAS
HY-114277 Sotorasib Marketed: NSCLC (2021)
Registered: CRC
Phase III: Solid tumours
Phase I/II: Brain metastases; Pancreatic cancer 		KRASG12C
HY-130149 Adagrasib Marketed: CRC; NSCLC (2022)
Phase II: Solid tumours
Phase I: Pancreatic cancer
Preclinical: Bladder cancer
HY-152848 Fulzerasib Marketed: NSCLC (2024)
Phase III: CRC
HY-139612 Opnurasib Phase I/II: Solid tumours
Phase I: Small-cell lung cancer (SCLC)
HY-160023 D3S-001 Phase II: CRC; NSCLC ; Pancreatic cancer
Phase I/II: Solid tumours
HY-145928 Divarasib Phase III: NSCLC
Phase I: Breast cancer; Solid tumours
HY-143589 Glecirasib Preregistration: NSCLC
Phase II: CRC; Pancreatic cancer
Phase I/II: Intestinal cancer; Solid tumours
HY-158107 BBO-8520 Phase I: NSCLC
HY-134813 MRTX1133 Phase I/II: Solid tumours
Preclinical: Multiple myeloma; Pancreatic cancer 		KRASG12D
HY-159127 HRS-4642 Phase I/II: Pancreatic cancer; Solid tumours
HY-156819 Zoldonrasib Phase I: Solid tumours
HY-173637 AZD0022 Phase I/II: Solid tumours
HY-156498 RMC-7977 N/A Pan-KRAS
HY-153724 BI-2865 N/A
HY-153723 BI-2493 N/A
HY-148439 RMC-6236 Phase III: Adenocarcinoma; Non-small cell lung cancer
Phase I/II: Pancreatic cancer
Phase I: Solid tumours
Targeted regulation of KRAS active protein
HY-125817 BI-3406 N/A SOS1
HY-114398 BAY-293 N/A
HY-134885 RMC-0331 N/A
HY-145926 MRTX0902 Phase I/II: Solid tumours
HY-136173 Batoprotafib Phase II: Solid tumours SHP2
HY-141523 RMC-4630 Phase II: NSCLC
Phase I/II: CRC; Solid tumours
HY-161952 JAB-3312 Phase III: NSCLC
Phase I/II: Solid tumours
HY-144903 Migoprotafib Phase I: NSCLC; Solid tumours
References
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 [Content Brief]
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 [Content Brief]
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[13] Pietrantonio, Filippo et al. J Clin Oncol. 2025 Apr 11:JCO2402026.
[14] Shubham Pant et al. JCO 41, 425082-425082(2023).
[15] Jänne, Pasi A et al. N Engl J Med. 2022 Jul 14;387(2):120-131.
[16] Yaeger, Rona et al. N Engl J Med. 2023 Jan 5;388(1):44-54.
[17] Hong, David S et al. N Engl J Med. 2020 Sep 24;383(13):1207-1217.
[18] Luo, Ziwei et al. Cancer Res. 2025 Jan 2;85(1):101-117.
 [Content Brief]
[19] Pancreatic Cancer Update. Retrieved October 25, 2024.
[20] VS-7375 (GFH375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy as single agent and in combination with other anticancer therapies in preclinical models.