Aug 2026· Cancer Research· Vol 86 16, pp.
3903-3905
· 0 citations· 10 references
Medicine
TL;DR
PERTACs that degrade the KRAS oncoprotein are a promising modality for the treatment of lung adenocarcinomas, and resistance to PROTACs may differ from conventional KRAS inhibitors, suggesting potential strategies for overcoming such resistance.
Abstract
Mutant KRAS inhibition has revolutionized the treatment of lung adenocarcinoma. Unfortunately, responses to this form of targeted therapy are often of limited duration because of the development of resistance. Targeted protein degradation, including using PROTACs (PROteolysis-TArgeting Chimeras), presents an alternative approach to targeting oncogenic drivers in cancer. In this issue of Cancer Research, Martín and colleagues developed a dTAG-KRASG12V syngeneic mouse model that allows for the study of the effects of degrading the KRASG12V oncoprotein in vivo. The authors discovered that degrading the KRASG12V oncoprotein leads to regression of the resulting lung adenocarcinoma tumors. Most of the regression was based on cancer cell-intrinsic responses, although the tumor microenvironment also underwent substantial remodeling. Despite the initial efficacy of the treatment, the authors found that prolonged PROTAC KRAS degrader treatment eventually resulted in relapse. Resistance to PROTAC treatment seemed to be driven by dysregulation of the ubiquitin-proteasome system that is required for the activity of the PROTAC degraders. Despite developing resistance to the PROTAC degraders, the resulting tumors were still dependent on the KRAS oncoprotein, meaning that they were still sensitive to conventional KRAS inhibitors. Thus, PROTACs that degrade the KRAS oncoprotein are a promising modality for the treatment of lung adenocarcinomas. Resistance to PROTACs may differ from conventional KRAS inhibitors, suggesting potential strategies for overcoming such resistance. See related article by Martín et al., p. 4115.
Alterations in KRAS are among the most common oncogenic drivers in solid tumors, including pancreatic, colorectal, and lung cancers, with G12D, G12V, and G12C representing the most frequent mutations. Unlike wild-type KRAS, which cycles between inactive and active states, mutant KRAS is constitutively active and drives uncontrolled proliferation and survival through downstream signaling. KRAS PROteolysis TArgeting Chimera (PROTAC) degraders are designed to eliminate the oncogenic protein, thereby stopping this dysregulated signaling cascade at the source. Their iterative mechanism, in which one PROTAC molecule can degrade multiple target proteins, may offer advantages over inhibitors, particularly in tumors with KRAS amplification, a common feature of KRAS-driven cancers and a resistance mechanism to inhibitor therapy. KRAS degradation may also produce deeper, more sustained pathway suppression and a distinct resistance profile compared with inhibition. Both mutation-selective and pan-KRAS PROTAC degraders have been identified and will be described herein. Both classes of PROTAC degraders target the ON and OFF forms of KRAS while sparing the related isoforms, HRAS and NRAS. ARV-806 is a PROTAC KRAS G12D-selective degrader currently being evaluated in a Phase1/2 clinical study (NCT07023731). Preclinically, ARV-806 demonstrated sub-nanomolar potency for degrading KRAS G12D and >25-fold greater anti-proliferative potency compared to inhibitors and another clinical-stage degrader. In vivo, ARV-806 induced robust KRAS G12D degradation that was sustained for >7 days after a single IV dose and produced tumor regressions across multiple models. Orally bioavailable PROTAC pan-KRAS degraders have also been identified that potently degrade common KRAS mutations like G12C/D/V, difficult-to-target variants such as G12R and Q61H, and amplified KRAS. In vitro, degradation led to potent antiproliferative activity and induction of apoptosis of KRAS-driven cells, with no observed impact on cells not driven by KRAS. In vivo, treatment with the PROTAC pan-KRAS degrader led to regressions in multiple tumor models bearing different KRAS mutations. Additionally, a sustained pharmacodynamic effect was observed with the PROTAC pan-KRAS degrader inducing prolonged suppression of KRAS protein levels and downstream signaling compared to an inhibitor. In a KRAS-mutant syngeneic model, pan-KRAS degradation combined with immune checkpoint inhibition produced more complete responses than a pan-RAS inhibitor combination, accompanied by increased cytotoxic T-cell and dendritic-cell infiltration, reduced myeloid populations, and enhanced immune checkpoint response gene signatures. Together, these findings support oral pan-KRAS degraders as a differentiated therapeutic approach for KRAS-driven cancers, with potential advantages in monotherapy activity, durability, immune engagement, and tolerability relative to pan-RAS targeting.
Kathryn D. Smith. Eliminating the oncogenic driver: Advancing targeted degradation of KRAS [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr IA05.
Kathryn D. Smith· Clinical Cancer Research· 0 citations
Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutations represent the most common driver alterations in non-small cell lung cancer and were long considered "undruggable" due to the lack of a suitable binding pocket on the protein surface. Recent structural breakthroughs have identified the Switch-II allosteric pocket, facilitating the development and clinical application of several covalent inhibitors—including Sotorasib, Adagrasib, and Divarasib—which have substantially improved outcomes for patients harboring this mutation. However, primary and acquired resistance remain major obstacles to long-term efficacy, with resistance mechanisms involving RTK-mediated adaptive signaling reactivation, aberrant PI3K–AKT–mTOR pathway activation, secondary genetic alterations, and other factors. Moreover, intratumoral heterogeneity, characterized by the coexistence of sensitive and resistant subclones, further complicates therapeutic responses. To overcome these challenges, combination strategies have become a major research focus, including the pairing of KRAS G12C inhibitors with immune checkpoint inhibitors, RTK-targeted agents, SHP2 inhibitors, or MEK inhibitors, aiming to block escape pathways and enhance antitumor immunity. Future directions emphasize optimizing combination regimens, exploring personalized immunotherapy, and developing next‑generation inhibitors to prolong survival. This review systematically summarizes the molecular mechanisms driving KRAS G12C‑mutant lung cancer, clinical applications of targeted drugs, resistance and heterogeneity challenges, and progress in combination therapy, providing a reference for clinical decision‑making and further research in this field.
Xizhi Zha· Theoretical and Natural Scie...· 0 citations
The introduction of tyrosine kinase inhibitors (TKIs) targeting driver oncogenes such as EGFR, ALK, and KRAS has substantially reshaped the treatment landscape of non-small cell lung cancer (NSCLC) and improved patient outcomes. However, inevitable acquired resistance remains the core obstacle to therapeutic success. Unlike previous studies that have largely focused on secondary mutations or bypass activation, the role of proteostasis imbalance in the evolution of resistance is increasingly recognized. The ubiquitin-proteasome system (UPS), as the central machinery for intracellular protein degradation and quality control, precisely regulates the stability, localization, and function of numerous key proteins, and is extensively involved in cell cycle progression, apoptosis, DNA damage repair, and various signaling pathways. Accumulating evidence indicates that UPS dysregulation is a critical factor in the emergence and maintenance of resistance to targeted therapy in NSCLC. By altering the expression and activity of specific E3 ligases or deubiquitinating enzymes (DUBs), resistant cells can remodel their proteome to achieve aberrant stabilization of pro-survival proteins, degradation of pro-apoptotic factors, or activation of alternative survival pathways, thereby adapting to TKI pressure. In light of this, developing interventions targeting core components of the UPS-such as next-generation proteasome inhibitors, molecular glues, PROTACs, and inhibitors of E3 ligases or DUBs-has emerged as a highly promising direction to overcome resistance. This review aims to systematically summarize the molecular mechanisms by which the UPS contributes to targeted therapy resistance in NSCLC, evaluate recent progress in emerging UPS-targeting strategies-most of which remain at preclinical or early clinical stages-and critically discuss the major barriers impeding their clinical translation, including off-target toxicity, selectivity issues, and the need for rationally designed combination regimens.
Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with about 50% of patients presenting with KRASG12D mutations. Small molecule inhibitors targeting KRASG12D suppress PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained efficacy of KRASG12D inhibition and mechanisms of resistance to KRASG12D suppression remain to be elucidated. Here, integrated spatial transcriptomics, single-cell RNA sequencing, and CODEX-based spatial proteomics analyses of PDAC mouse models uncover that while KRASG12D inhibition by MRTX1133 initially increases CD11c+ cells and T cell infiltration proximal to cancer cells, long-term treatment results in reversal of the immune responses leading to resistance promoted by multiprotein mediator complex associated kinase CDK8. CDK8 imparts this resistance via induction of CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself or in combination with αCTLA-4 immunotherapy overcomes resistance to KRASG12D inhibition. We also provide evidence of CDK8 upregulation in PDX tumors resistant to inhibitors selective for RAS(ON) and RASG12D(ON): daraxonrasib and zoldonrasib, respectively, highlighting a common KRAS vulnerability node for TME resistance. Targeting of oncogenic KRAS mutations suppresses cancer growth, however relapse arises by unclear mechanisms. This study identifies mediator complex kinase CDK8 as a driver of resistance towards KRASG12D inhibition in pancreatic ductal adenocarcinoma (PDAC), promoting stromal remodeling and immunosuppression. Priming with oncogenic KRAS inhibitors and subsequent combination treatment with checkpoint immunotherapy significantly delays or prevents resistance. Long-term inhibition of oncogenic KRAS alone induces eventual therapy resistance in PDAC mouse models. CDK8 is upregulated in PDX tumors resistant to inhibitors selective for RAS(ON) and RASG12D(ON) protein states, Daraxonrasib and Zoldonrasib, respectively. CDK8 mediates KRAS inhibition resistance via reprogramming the tumor microenvironment and deficiency in immunological memory response. CDK8 confers resistance by re-initiating suppression of FAS expression and inducing secretion of the chemokine CXCL2. Targeting CDK8 overcomes resistance to KRASG12D inhibition. While tumors resistant to oncogenic KRAS inhibition also lose the ability to respond to anti-CTLA-4 immunotherapy, CDK8 inhibition in resistant tumors re-primes PDAC to anti-CTLA-4 immunotherapy efficacy. Priming with oncogenic KRAS inhibitors and subsequent combination treatment with checkpoint immunotherapy significantly delays or prevents resistance. Long-term inhibition of oncogenic KRAS alone induces eventual therapy resistance in PDAC mouse models. CDK8 is upregulated in PDX tumors resistant to inhibitors selective for RAS(ON) and RASG12D(ON) protein states, Daraxonrasib and Zoldonrasib, respectively. CDK8 mediates KRAS inhibition resistance via reprogramming the tumor microenvironment and deficiency in immunological memory response. CDK8 confers resistance by re-initiating suppression of FAS expression and inducing secretion of the chemokine CXCL2. Targeting CDK8 overcomes resistance to KRASG12D inhibition. While tumors resistant to oncogenic KRAS inhibition also lose the ability to respond to anti-CTLA-4 immunotherapy, CDK8 inhibition in resistant tumors re-primes PDAC to anti-CTLA-4 immunotherapy efficacy. Mediator complex kinase CDK8 is a novel common vulnerability for stromal resistance towards oncogenic RAS inhibition in pancreatic cancer.
Kathleen M. McAndrews, Krishnan K. Mahadevan, Bingrui Li et al.· EMBO Journal· 1 citation
Direct KRAS inhibitors have established mutant KRAS as a clinically actionable target, yet adaptive resistance remains a major barrier to durable responses. To identify therapeutically actionable resistance mechanisms, we performed an unbiased in vivo CRISPR activation screen in an autochthonous lung adenocarcinoma model, identifying the receptor tyrosine kinase AXL as a dominant adaptive resistance driver. Pharmacologic AXL inhibition enhanced the efficacy of both allele-specific inhibition and the RAS(ON) multi-selective inhibitor daraxonrasib across lung and pancreatic cancer models, resulting in deeper and more durable suppression of MAPK signaling and improved tumor control. Beyond tumor-intrinsic effects, combined KRAS and AXL inhibition remodeled the tumor immune microenvironment, promoting an IFNγ-responsive program, increased recruitment of cytotoxic T cells and sensitization to FAS-mediated apoptosis. Collectively, our findings identify AXL as a convergence point for adaptive resistance to KRAS inhibition and provide a mechanistically informed combination strategy to extend the durability of KRAS-directed therapies. Statement of Significance An unbiased in vivo functional (CRISPR activation) screen identifies AXL as a convergence point for adaptive resistance to KRAS inhibition. By integrating adaptive response to KRAS inhibition with anti-tumor immunity, AXL represents a mechanistically actionable vulnerability whose inhibition deepens and prolongs responses to both allele-specific and pan-KRAS-targeted therapies.
F. Thege, A. Kramer, Norbert Kreisz et al.· bioRxiv· 0 citations
Combination targeted therapy with BRAF/MEK inhibitors and immune therapy show promising therapeutic outcomes in melanoma; however, the development of drug resistance still represents a formidable challenge. Remaining unexplored is the possibility that BRAF/MEK inhibitors themselves inadvertently compromise the tumor immune microenvironment, limiting the efficacy of immunotherapy when it is used in combination with targeted inhibitors. Herein, we profiled the landscape of the BRAF regulatome identifying a novel transcription factor, TFAP2A, newly linking BRAF/MEK drug resistance to antitumor immunity. Specifically, we found that BRAF/MEK inhibitors significantly upregulate TFAP2A. Further, genetic disruption of TFAP2A overcomes BRAF/MEK-inhibitor resistance, promotes stromal enrichment, and enhances intratumoral infiltration of macrophages in an immune-compromised mouse model. In a syngeneic mouse model, TFAP2a knockout not only suppresses tumor growth but also induces potent anti-tumor tertiary lymphoid structures (TLSs). Single cell transcriptomics revealed that the absence of TFAP2A shapes the antitumor microenvironment with an influx of M1-like macrophages, CD8+ T cells and mature dendritic cells. By identifying TFAP2A as a shared driver of both targeted therapy resistance and immunosuppression, our work offers a one-stone-two-bird strategy to overcome drug resistance and elicit antitumor immunity.
Haiwei Mou, Veronika Yakovishina, Kristen M DeRosa et al.· bioRxiv· 0 citations