These findings highlight the potential of purine-based KRAS G12D inhibitors as candidates for targeted cancer therapy. However, further exploration and optimization of these compounds are essential to meet the unmet clinical needs of patients with KRAS-mutant cancers.

Recently, sotorasib and adagrasib were approved as treatment options for advanced NSCLC with KRASG12C mutations. Therefore, KRASG12C inhibitors may be a safe and effective treatment option for NSCLC with comorbid IP. This review article discusses the promise and prospects of molecular-targeted therapies, especially KRASG12C inhibitors, for NSCLC with comorbid IP, along with our own clinical experience.

The discovered noncovalent KRASG12D inhibitors exhibit promises as potential candidates for targeted therapy against KRASG12D-driven cancers. This comprehensive computational framework not only expedites the discovery of novel KRASG12D inhibitors but also provides valuable insights for the development of precision treatments tailored to this oncogenic mutation.

No abstract available

However, achieving this synergy in the clinical setting has proven challenging. Here, we explore how understanding the impact of RAS mutant tumor cells on the TME can guide innovative approaches to combining RAS inhibition with immunotherapies, review progress in both pre-clinical and clinical stages, and discuss challenges and future directions.

The histologic transformation of adenocarcinoma (ADC) to squamous cell carcinoma (SCC), known as adeno-squamous transition or AST, is frequently observed in patients with lung cancer undergoing cancer therapy. In this issue, Tong and colleagues investigate genetic and epigenetic mechanisms that drive AST to confer resistance to KRAS inhibitors in preclinical models and patients.

P2, N=0, Withdrawn, National Cancer Institute (NCI) | N=210 --> 0 | Trial completion date: Dec 2029 --> Mar 2024 | Not yet recruiting --> Withdrawn | Trial primary completion date: Dec 2028 --> Mar 2024

Inhibition of Polo-like kinase 1 (Plk1) is a promising new target and therapeutic strategy in metastatic colorectal cancer, especially those with KRAS mutations. New data support further development of onvansertib, and highlights the role of circulating tumor DNA in phase 1 clinical trials.

P1, N=30, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Dec 2024 --> Aug 2025 | Trial primary completion date: Dec 2024 --> Aug 2025

Additionally, % occupancies, bond angles and the length of hydrogen bonds were calculated. These findings suggest that Azacitidine and Ribavirin may potentially serve as candidates for repurposing in individuals with KRAS-dependent cancers.Communicated by Ramaswamy H. Sarma.

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

We find that the combination of sotorasib, a drug targeting KRASG12C, and the MAP2K4 inhibitor HRX-0233 prevents this feedback activation and is highly synergistic in a panel of KRASG12C-mutant lung and colon cancer cells. Moreover, combining HRX-0233 and sotorasib is well-tolerated and resulted in durable tumor shrinkage in mouse xenografts of human lung cancer cells, suggesting a therapeutic strategy for KRAS-driven cancers.

P1, N=210, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

Most inhibit intrinsic and/or SOS-mediated KRAS activation while others inhibit RAS-effector interaction. We propose these compounds as starting points for the development of non-covalent allosteric KRAS inhibitors.

In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.

P1, N=210, Not yet recruiting, National Cancer Institute (NCI)

P1, N=250, Recruiting, Quanta Therapeutics | Not yet recruiting --> Recruiting

Importantly, the combination of 23 with AMG510 suppressed RAS signaling feedback activation, showing synergistic effects against KRASG12C mutant cells in vitro and in vivo. Our findings demonstrated that KRASG12C inhibition plus SOS1 degradation as a potential therapeutic strategy to improve antitumor response and overcome acquired resistance to KRASG12C inhibitor.

The development of KRAS G12C mutant conformational modulators and the introduction of Sotorasib (R&D code: AMG510) have been a breakthrough in this field, with its remarkable clinical outcomes...This review classifies KRAS G12C inhibitors based on their chemical structure and evaluates their biological properties. Additionally, it discusses the obstacles encountered in KRAS inhibitor research and the corresponding solutions.

P1, N=52, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

Further investigation of the immunological response using single-cell sequencing and multispectral imaging revealed that tumor regression was associated with suppression of neutrophils and influx of effector CD8+ T cells. Together, these findings demonstrate that both tumor cell-intrinsic and extrinsic events contribute to response to MRTX1133 and credential KRASG12D inhibition as a promising therapeutic strategy for a large percentage of PDAC patients.

Our findings warrant the clinical exploration of KRAS-G12C inhibitors in combination with farnesyl-transferase inhibitors.

P2, N=20, Ongoing, Jacobio Pharmaceuticals Co., Ltd.

P1, N=250, Not yet recruiting, Quanta Therapeutics

Ectopic expression of AURKA attenuated the effect of KRAS inhibitors on the expression of GLI-1 and re-expression of KRAS. Together, these findings demonstrate the important role of AURKA, primary cilia, and Hedgehog signals in the re-expression of KRAS and therefore the induction of acquired resistance to KRAS inhibitors, and provide a rationale for targeting Hedgehog signalling to overcome acquired resistance to KRAS inhibitors.

We show that binding of this inhibitor significantly perturbs the state 1 - state 2 equilibrium and induces an inactive state 1 conformation in GTP-bound KRAS G12C. In the presence of BBO-8956, RAF1 RBD is unable to induce a signaling competent state 2 conformation within the ternary complex, demonstrating the mechanism of action (MOA) for this novel, active-conformation inhibitor.

In this report, we describe the design and evaluation of potent and KRAS G13D-selective reversible inhibitors. Subnanomolar binding to the GDP state Switch II pocket and biochemical selectivity over WT KRAS are achieved by leveraging a salt bridge with D13.

Combination of GMI and KRAS inhibitor, AMG 510, resulted in more durable inhibition of tumor growth and KRAS activity in H358 cells-xenograft mice. This study highlights the potential of GMI, a dietary fungal protein, as a viable therapeutic avenue for KRAS-mutant lung cancer in combination with KRAS inhibitors.

No abstract available

Cancer vaccine ELI-002 2P enhances lymph node delivery and immune response using amphiphile (Amph) modification of G12D and G12R mutant KRAS (mKRAS) peptides (Amph-Peptides-2P) together with CpG oligonucleotide adjuvant (Amph-CpG-7909). ELI-002 2P was safe and induced considerable T cell responses in patients with immunotherapy-recalcitrant KRAS-mutated tumors. ClinicalTrials.gov identifier: NCT04853017 .

The recently approved KRAS mutation-specific inhibitors sotorasib and adagrasib (KRAS-I) represent a promising therapy for KRAS-driven non-small cell lung cancer (NSCLC)...Tissue factor (TF) is overexpressed in KRAS-mutated (KRASmut) NSCLC and is the target of the FDA-approved ADC Tivdak...Thus, we have identified the TF/mTORC2 axis as a critical new mechanism for triggering immunosuppression and KRAS-I resistance. We propose that targeting this axis with HuSC1-39 or MTI-31 will improve KRAS-I response in KRAS-driven NSCLC.

This study provided a comprehensive understanding of the efficacy and safety of KRAS inhibitors in treating solid tumors and identified KEAP1 mutation as a potential predictive biomarker of inferior response in patients treated with KRAS inhibitors. These findings may assist in the design of future clinical trials for identifying populations that may benefit from KRAS inhibitor treatment.

In this report, we further optimized the substituents on the quinazoline scaffold based on the structure-based drug design from the co-crystal structure analysis of compound 1 and KRAS G12C to enhance in vitro activity. As a result, ASP6918 was found to exhibit extremely potent in vitro activity and induce dose-dependent tumor regression in an NCI-H1373 xenograft mouse model after oral administration.

P1, N=25, Active, not recruiting, Elicio Therapeutics

While coinhibition of KRASG12C and YAP/TAZ did not cause complete tumor regression in xenograft models, combining YAP/TAZ inhibition was capable of significantly extending the response of tumors to KRASG12C inhibition. See related articles by Mukhopadhyay et al., p. 4095, Edwards et al., p. 4112, and Prahallad et al., p. 4130.

Erlotinib was used as internal standard and acetonitrile was utilized to treat 10 µl of the sample with protein precipitation in a 96-well plate format. Opnurasib in mouse plasma was stable up to 12 h at room temperature, and up to 8 h at room temperature in tissue homogenates (except for kidney up to 4 h). This presented method has been successfully applied to quantify opnurasib in preclinical samples from a mouse study and demonstrated its usability to support preclinical pharmacokinetic studies.

Our study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRASi and represents a promising therapeutic target for combination strategies with KRASi in the treatment of KRAS-mutant cancers.

TBD

The results obtained in this work showed a profound inhibition of tumor growth, which was associated with a reduction in cell proliferation, an increase in apoptosis, and a reduction in the MAPK and PI3K/AKT/mTOR signaling pathways. In conclusion, these results demonstrate the high potency and efficacy of MRTX1133 in KRAS-PMP tumors and provide a rationale for clinical trials.

Glecirasib monotherapy is well tolerated and has a manageable safety profile and exhibits promising anti-tumor activity in pts with KRAS G12C mutated PDAC and other solid tumors. Further clinical development of glecirasib in above mentioned population is ongoing (NCT06008288). Clinical trial information: NCT05009329 and NCT05002270.

In pts with GI tumors, LY3537982 alone or in combination with cetuximab demonstrated preliminary efficacy and a favorable safety profile. Clinical trial information: NCT04956640. >aEfficacy evaluable pts are those who had at least 1 post-baseline response assessment or had discontinued treatment before the first post-baseline assessment.bDCR = PR+SD.c1 CRC, 2 PANC, and 1 duodenal cancer pt (other GI) have unconfirmed PR, ongoing and pending confirmation.dOther GI includes duodenal cancer (n=3), small intestine (n=2), esophageal cancer, jejunal adenocarcinoma (both n=1).e1 pt with small intestine cancer is not yet evaluable.f8 pts are not yet evaluable.g3 pts have unconfirmed PR, ongoing and pending confirmation.

ELI-002 2P is a lymph node targeted immunotherapy comprised of Amphiphile (Amph)-modified G12D, G12R, G12V, G12C, G12A, G12S and G13D mutant KRAS peptides together with an Amph-modified CpG oligonucleotide adjuvant...Subsequent patients will receive up to 10 doses of Amph-peptides 7P 700 mcg each (4.9 mg total), together with Amph-CpG-7909 (10.0 mg) administered over a five-month treatment period...An interim analysis is planned using group sequential design for control of overall alpha 0.10. Clinical trial information: NCT05726864.