Targeting the undruggable: Updates in KRAS directed therapies

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Chris Wang

Since its discovery in 1982, therapies targeting the mutated KRAS oncogene have long eluded cancer researchers. KRAS has been considered an undruggable target for decades due to lack of a binding pocket where a drug could fit.¹ However, the need for KRAS targeting therapies is severely needed as KRAS mutations dominate the landscape of many solid tumors including lung, colorectal, pancreatic, and ovarian cancers.¹ 

KRAS is a protein involved in many cellular growth signaling pathways. The ability for wild type KRAS to cycle between its activated (GTP bound) and inactivated states (GDP bound) is tightly regulated.¹ However, point mutations in three spots involving the amino acid residues G12, G13, and Q61 cause KRAS to always be in its active conformation.¹ These known mutations maintain the activated confirmation and promote downstream signaling for growth (RAF–MEK–ERK) and survival without prior stimulation.¹

In 2021, the first KRAS targeting inhibitor, sotorasib, was granted accelerated approval for advanced stage non-small cell lung cancer (NSCLC) with a KRAS G12C mutation.² The mechanism for how sotorasib was able to overcome the limitations earlier KRAS inhibitors could not was because it specifically targeted the unique cysteine residue of the mutant KRAS G12C protein.² Cysteine can form an irreversible bond with a drug that contains an unsaturated carbonyl group, such as the one in sotorasib. Quickly following sotorasib, another G12C inhibitor, adagrasib, landed an accelerated approval in both NSCLC (when used alone) and advanced stage colorectal cancer (CRC) (when used in conjunction with an EGFR inhibitor called cetuximab).³ Cancer researchers initially studied KRAS inhibition alone in CRC but failed to account for upregulation of EGFR signaling (by KRAS) which led to poor anticancer efficacy.^2,3 Only after studying KRAS inhibition alongside EGFR blockade did KRAS inhibitors achieve meaningful clinical benefit in CRC.^2,3 

Despite these successes, many cancer patients with KRAS mutations are unable to benefit from currently approved therapies. The vast majority of KRAS mutations in colorectal, pancreatic, and ovarian cancer are not of the G12C variant and thus cannot be targeted with sotorasib or adagrasib.¹ Additionally, up to 60% of lung cancer patients with KRAS G12C do not respond to sotorasib or adagrasib.^2,3 To overcome these challenges, researchers are coming up with treatment modalities that target KRAS in novel ways (Figure 1).

One modality includes multi-selective inhibition of the active form of RAS. Daraxonrasib, also known as RMC-6236, is a broad spectrum inhibitor of mutant KRAS.⁴ When it interacts with both the intracellular chaperonin protein cyclophilin A (CypA) and with active KRAS to form a tricomplex, it blocks binding of downstream KRAS activators via steric hindrance.⁴ In both preclinical models and small phase 1 studies in NSCLC and pancreatic cancer, daraxonrasib was able to demonstrate sustained KRAS inhibition and preliminary anti-cancer efficacy in all forms of mutated KRAS including KRAS G12X, G13X, and Q61X.⁴ Ongoing phase 3 studies are comparing daraxonrasib to the standard of care for KRAS-mutated advanced stage pancreatic cancer and NSCLC in the second line of treatment.

Another approach utilizes the immune system to recognize KRAS mutations through a cancer vaccine. Mutated KRAS is an attractive target for the immune system because its expression is restricted to only tumor cells and not normal tissues.⁵ Even though KRAS is an intracellular protein, recent advances in immune therapy allow T-cells primed to target mutated KRAS to recognize these tumor cells and target them for destruction.⁵ Researchers are currently investigating cancer vaccines targeting mutant KRAS to prevent recurrence in patients with surgically removed KRAS-mutated pancreatic and colorectal cancers. An example of this includes the ELI-002 vaccine, which utilizes mutant KRAS fragments attached to albumin-binding lipids, co-formulated with a DNA-based adjuvant designed to boost the immune system.⁵ Such a vaccine could promote the immune system to find and eliminate leftover tumor cells that express mutant KRAS proteins and overcome limitations from previously failed cancer vaccines. Ongoing clinical trials are studying ELI-002 in various KRAS mutated solid tumors with phase 1 trial data demonstrating preliminary anticancer effects, mainly via reductions in circulating tumor markers within the blood.⁵

Lastly, an approach that targets downstream and parallel pathways of RAS, including MEK and FAK, has just landed a new FDA accelerated approval. MEK and FAK are both protein kinases which promote cellular growth. While MEK is a downstream effector protein of RAS, FAK is thought to signal through separate but synergistic growth pathways.⁶ Up to half of all patients with low grade serous ovarian cancer (LGSOC) have mutations in the KRAS pathway but previous trials investigating single-agent MEK inhibition in RAS-mutated LGSOC failed to show enough benefit to gain FDA approval.⁶ To overcome this, dual inhibition with both avutometinib (MEK inhibitor) and defactinib (FAK inhibitor) was studied in the phase 2 RAMP-201 trial which demonstrated tumor shrinkage in 44% of patients with KRAS-mutated LGSOC.⁷ Based on this preliminary data, a coformulation of avutometinib + defactinib was granted accelerated FDA approval for recurrent, KRAS-mutated, LGSOC in May 2025.⁷ An ongoing phase 3 RAMP-301 trial of avutometinib + defactinib in LGSOC is underway to confirm its benefit.⁶

Ongoing research is needed to fill the gaps in treated KRAS-mutated solid tumors. Researchers and cancer patients remain motivated to see whether novel KRAS-targeting treatments such as tricomplex RAS/CypA inhibitors, KRAS-mutant vaccines, and inhibition of downstream/parallel kinase pathways can meet these needs.

Year	Agent	FDA Approval Type	FDA Approved Cancer Type
2021	Sotorasib	Accelerated (Preliminary)	KRAS G12C mutated advanced stage NSCLC
2022	Adagrasib	Accelerated (Preliminary)	KRAS G12C mutated advanced stage NSCLC
2023	Sotorasib	Full	KRAS G12C mutated advanced stage NSCLC
2024	Adagrasib	Accelerated (Preliminary)	KRAS G12C mutated advanced stage CRC (in combination with cetuximab, an EGFR inhibitor)
2025	Sotorasib	Full	KRAS G12C mutated advanced stage CRC (in combination with panitumumab, an EGFR inhibitor)
2025	Avutometinib + Defactinib	Accelerated (Preliminary)	KRAS mutated recurrent low-grade serous ovarian cancer (LGSOC)

Table 1. Timeline of KRAS targeting anti-cancer agents

Header Image Source: cropped section of Figure 1

Figure 1 Source: Created by author using Biorender.com

Edited by Celia Snyman

References

1. Huang L, Guo Z, Wang F, Fu L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther. 2021 Nov 15;6(1):386. 
2. Lumakras (sotorasib) [package insert].Thousand Oaks, CA: Amgen Inc.; 2025.
3. Krazati (adagrasib) [package insert]. Princeton, NJ: Bristol-Meyers Squibb Co.; 2025.
4. Jiang J, et al. Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discov. 2024 Jun 3;14(6):994-1017. 
5. Pant S, et al. Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial. Nat Med. 2024 Feb;30(2):531-542. 
6. Grisham R, et al. GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301: a phase 3, randomized trial evaluating avutometinib plus defactinib compared with investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer. Int J Gynecol Cancer. 2025 Jan 6:ijgc-2024-005919. 
7. Avmapki Fakzynja Co-pack (avutometinib; defactinib) [package insert]. Needham, MA: Verastem Inc.; 2025.

Abbreviations
KRAS: Kirsten rat sarcoma virus

GTP: Guanosine triphosphate

NSCLC: Non-small cell lung cancer

CRC: Colorectal cancer

EGFR: Epidermal growth factor receptor

DNA: Deoxyribonucleic acid

LGSOC: Low grade serous ovarian cancer

MEK: Mitogen activated protein kinase kinase

FAK: Focal adhesion kinase