Overcoming clinical resistance to KRAS inhibition: Pan-RAS degraders may be a potential alternative strategy in the future
Year: 2025
Type: article
Abstract: As demonstrated in our recent publication, the proto-oncogene Kirsten rat sarcoma virus (KRAS) is frequently mutated at codons 12, 13, and 61, with these alterations promoting tumor progression by stabilizing KRAS in its active, guanosine triphosphate (GTP)-bound conformation.[1] Despite the recent approval of small-molecule inhibitors targeting KRASG12C, such as sotorasib and adagrasib—drugs that bind to a pocket in the switch II region when KRAS is in its inactive, guanosine diphosphate (GDP)-bound state (KRAS[OFF] inhibitors)—recent clinical data indicate that nearly all patients who initially respond to these therapies ultimately develop drug resistance.[2–4] As highlighted in our recent report published in the Journal of Hematology & Oncology, secondary rat sarcoma virus (RAS) mutations were identified as the third most common cause of primary resistance.[1] In acquired resistance, KRAS alterations—such as G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and KRASG12C amplification—ranked second [Figure 1].[1] In addition, we summarized adaptive resistance as follows: Targeting the KRAS “OFF” state suppresses the mitogen-activated protein kinase (MAPK) pathway, disrupting feedback inhibition and resulting in upregulation of receptor tyrosine kinases (RTKs). This upregulation drives a shift of RAS into the “ON” state, mediated by son of sevenless (SOS) and src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2), which activates wild-type (WT) RAS isoforms and initiates rebound signaling, ultimately attenuating the efficacy of the drug [Figure 1].[1] Recent studies published in Science have made a significant breakthrough in cancer therapeutics, particularly in targeting the notoriously challenging KRAS oncogene.[5]Figure 1: The pan-RAS degrader may serve as a promising alternative strategy for overcoming clinical resistance to KRAS inhibition. Pan-RAS degrader is a degrader developed through a structure-based design approach that optimizes the stability and durability of the E3 ubiquitin ligase: PROTAC: RAS ternary complex. Current clinical resistance mechanisms are typically associated with secondary or acquired mutations of RAS or the activation of adaptive wild-type RAS. Therefore, a pan-RAS degrader may provide a valuable strategy for addressing these resistance mechanisms in the future. G12, T35, and Q61, as shown in the figure, represent key amino acid residues that maintain the functional state of KRAS. GAP: GTPase-activating protein; GEF: Guanine nucleotide exchange factor; HRAS: Harvey rat sarcoma virus; KRAS: Kirsten rat sarcoma virus; NRAS: Neuroblastoma rat sarcoma virus. PROTAC: Proteolysis-targeting chimera; RAS: Rat sarcoma virus; RTK: Receptor tyrosine kinase; WT: Wild type.Popow et al[5] described the development of a proteolysis-targeting chimera (PROTAC). Leveraging biophysical and structural insights into ternary complexes, Popow et al designed a heterobifunctional small molecule capable of efficiently degrading 13 of the 17 most prevalent KRAS mutant alleles, as well as wild-type KRAS (KRASWT), with single-digit nanomolar potency. This KRAS degradation strategy selectively halts oncogenic signaling more efficiently than traditional inhibitors, offering superior potency and durability in KRAS-dependent cell lines. The enhanced efficacy is attributed to KRAS degradation via ubiquitin ligase recruitment, which achieves over 10-fold greater potency than inhibition alone, leading to prolonged suppression of MAPK signaling. To ensure effective in vivo concentrations, the researchers optimized ACBI3 to maintain key elements of ternary complex molecular recognition. ACBI3 was developed using a structure-based design approach aimed at enhancing the stability and durability of the von Hippel-Lindau (VHL):PROTAC:KRAS ternary complex. Due to its poor oral bioavailability, ACBI3 was formulated in a mixture of PEG-400/Transcutol/Kolliphor HS 15, allowing for multiple daily subcutaneous doses with a delayed absorption profile. When administered subcutaneously at 30 mg/kg to GP2d tumor-bearing mice—genetically modified to express specific KRAS mutations, such as KRASG12D, which closely mimic human KRAS-driven cancers—ACBI3 resulted in 44% degradation of KRASG12D in tumors compared to untreated controls. Daily subcutaneous dosing for up to two weeks led to significant tumor regression, achieving 127% tumor growth inhibition and a statistically significant difference between treatment and control groups. Although the formulation was well tolerated systemically, it did cause skin lesions in subcutaneous efficacy studies. To address this, the researchers transitioned to intraperitoneal administration of ACBI3 as a nano-milled suspension. This formulation induced tumor regressions in the KRASG12VTP53R175H mutant RKN xenograft model. Notably, a daily dose of 180 mg/kg of BI-2493, the first KRAS inhibitor targeting a broader spectrum of KRAS alleles compared to currently validated inhibitors, also induced tumor regressions in the same model. ACBI3 effectively targets a wide range of KRAS variants, presenting new opportunities for degraders to overcome resistance mechanisms associated with KRAS mutations, thus complementing the effect of direct pan-KRAS inhibitors. Pan-KRAS inhibitors block KRAS function, typically by targeting specific mutations (e.g., G12C), preventing KRAS from binding to GTP and thereby inhibiting downstream signaling pathways such as MAPK and PI3K/AKT. However, this inhibition can trigger compensatory activation of other signaling pathways or alternative mechanisms, such as the activation of Harvey rat sarcoma virus (HRAS) or neuroblastoma rat sarcoma virus (NRAS), leading to “rebound signaling”. This feedback activation, often involving other KRAS isoforms or upstream receptors like epidermal growth factor receptor (EGFR), can restore or even enhance signaling through parallel pathways, ultimately diminishing the therapeutic effect and contributing to drug resistance [Figure 1]. In contrast, pan-KRAS degraders, such as PROTACs, induce the complete degradation of KRAS proteins by recruiting them to the ubiquitin-proteasome system, resulting in sustained depletion of KRAS and a more profound disruption of KRAS-mediated signaling. Despite this, the loss of KRAS can still activate compensatory mechanisms, including the upregulation of other RAS isoforms or parallel signaling pathways, leading to the reactivation of downstream effects. However, unlike conventional inhibitors, degraders can bypass many of the resistance mechanisms associated with inhibition, offering a potential strategy to counteract resistance in KRAS-driven cancers. Of note, the novel degraders designed by Popow et al do not appear to target HRAS and NRAS. Therefore, future efforts should focus on developing pan-RAS degraders that include HRAS and NRAS, enabling more effective treatment of tumors with RAS mutations. Such an approach could also help address adaptive resistance mechanisms, particularly those arising from the activation of RASWT isoforms in HRAS and NRAS, which contribute to MAPK pathway signaling and limit the efficacy of KRAS-targeted therapies [Figure 1]. The insights gained from this study provide a fresh perspective on tackling the persistent challenge of drug resistance, a major hurdle in the clinical application of current KRAS inhibitors such as sotorasib and adagrasib. As outlined in our previous publication,[1] it is clear that most current clinical resistance mechanisms are linked either to secondary or acquired mutations, or amplifications of KRAS, or to the activation of adaptive RASWT, which enables tumor cells to resist treatment with KRAS inhibitors. By targeting RAS through a novel approach—specifically, the degradation of both mutant and RASWT—this new strategy has the potential to bypass existing resistance mechanisms. It offers a promising complementary or alternative method for overcoming resistance to current therapies [Figure 1]. Furthermore, while the combination of therapies—such as pan-KRAS inhibitors with HRAS/NRAS inhibitors, or KRAS inhibitors with MEK inhibitors and radiation—have the potential to overcome resistance mechanisms associated with KRAS mutations by targeting complementary or parallel signaling pathways,[6,7] thereby mitigating some limitations of a single-agent approach, we also emphasize the unique potential of a single-agent pan-RAS degrader as a more durable and comprehensive therapeutic strategy. The key advantage of pan-RAS degraders lies in their ability to directly induce the degradation of RAS, resulting in sustained suppression of RAS-mediated signaling. This strategy reduces the likelihood of resistance mechanisms, as the complete elimination of the protein minimizes the potential for compensatory feedback loops or the activation of other RAS isoforms—issues commonly encountered with inhibitors. Therefore, although combination therapies can help address resistance issues and enhance treatment effects, we believe that the development of a single pan-RAS degrader may provide a more direct, long-lasting, and comprehensive solution. This approach could circumvent some of the complexities associated with multi-drug regimens and potentially offer better control over resistance mechanisms in KRAS-driven cancers. Therefore, although we do not entirely dismiss combination therapies, we advocate for the exploration of pan-RAS degraders as a potentially more effective and enduring strategy in the treatment of KRAS-driven cancers. Notably, although pan-RAS degraders show promise in overcoming the limitations of traditional KRAS inhibitors, several challenges remain. A major hurdle is improving oral bioavailability, as many small-molecule degraders, including those targeting RAS proteins, suffer from poor absorption and low bioavailability. Enhancing their pharmacokinetic profiles through chemical modifications or advanced delivery systems could improve clinical viability and patient adherence. In addition, although pan-RAS degraders promote the complete degradation of RAS, this can trigger compensatory mechanisms that engage multiple signaling pathways, potentially leading to resistance that is more difficult to overcome than that associated with simple inhibition. Tumor cells may adapt by compensating with alternative RAS isoforms or activating other signaling routes. Combining pan-RAS degraders with agents targeting parallel pathways could address this issue; however, such combinations may introduce complexities, including drug interactions and side effects. Moreover, the toxicity and off-target effects of pan-RAS degraders warrant careful consideration. Targeting multiple RAS isoforms or related proteins could narrow their therapeutic window. Finally, efficient delivery and tumor penetration—especially in solid tumors—remain significant hurdles. Developing advanced delivery systems, such as nanoparticles, and optimizing dosing regimens could help overcome these challenges. In conclusion, while pan-RAS degraders represent an exciting approach to addressing clinical resistance to KRAS inhibitors in KRAS-driven cancers, a thorough exploration of their limitations—such as bioavailability, targeting of HRAS/NRAS, resistance mechanisms, toxicity, and delivery—would provide a more comprehensive understanding of their potential in clinical settings. Addressing these challenges could eventually make pan-RAS degraders become a cornerstone of targeted cancer therapy. In summary, this work highlights both promising new approaches and vital insights into potential challenges, establishing a strong foundation for future research and development. Although ACBI3 has demonstrated the ability to overcome resistance mechanisms associated with current KRAS inhibitors, it does not target HRAS and NRAS, which also play critical roles in mediating adaptive resistance. In addition, its lack of oral bioavailability presents a significant limitation. Therefore, future efforts on drug development that address these defects—specifically through the development of pan-RAS degraders, despite their own challenges that should not be neglected—could provide a novel strategy to more effectively overcome drug resistance while also offering enhanced convenience for patients with KRAS-driven cancers. Funding This work was supported by a grant from the Postdoctoral Research Fund of West China Hospital, Sichuan University (2025HXBH050). Conflicts of interests None.
Source: Chinese Medical Journal
Authors: Xiaojuan Yang, Jiang Zhu, Hong Wu
Institutions: Sichuan University, West China Hospital of Sichuan University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,000
OpenAlex ID: W4415836107