Targeting KRAS in cancer

Singhal, Anupriya; Li, Bob T.; O’Reilly, Eileen M.

doi:10.1038/s41591-024-02903-0

Cited by 33 publications

(13 citation statements)

References 129 publications

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“…Historically considered undruggable, KRAS -mutant NSCLC now has two approved targeted therapies as well as other potential therapeutic agents that are still under clinical development ( 10 , 13 , 19 – 22 ). This recent milestone in modern medicine was achieved thanks to the discovery of the allosteric regulatory site of KRAS G12C, thereby leading to the design of irreversible covalent inhibitors ( 23 ).…”

Section: Clinical Evidence For Kras Inhibition In Kras ...mentioning

confidence: 99%

“…In addition to sotorasib and adagrasib, several other direct KRAS G12C inhibitors, such as divarasib (GDC-6063), opnurasib (JDQ-443), garsorasib (D-1553), olomorasib (LY3537982), MK-1084, and JAB-21822 are now in clinical development as monotherapy or in combination with other treatments, as discussed in several recently published reviews ( Tables 2 , 3 , Figure 1 ) ( 10 , 13 , 20 – 22 , 82 – 84 ). A very recent review touches quite comprehensively and thoughtfully on the manifold combinatorial therapeutic strategies in RAS-driven cancers ( 84 ).…”

Section: Novel Direct Kras G12c Inhibitorsmentioning

confidence: 99%

“…The biological mechanism of resistance mediated by these mutations has yet to be explored. Co-occurring mutations that predict response to treatment might serve as markers for patient stratification and therapy intensification in randomized clinical trials ( 10 ).…”

Section: Mechanisms Of Resistance To Kras Inhibitionmentioning

confidence: 99%

“…Most notably, lung adenocarcinoma (LUAD) harbors those driver mutations and rearrangements that can be therapeutically addressed, such as EGFR , BRAF , ALK , ROS1 , RET , NTRK , and also KRAS ( 6 , 7 ). Mutations in the KRAS (Kirsten rat sarcoma virus) gene occur in approximately 29–32% of LUAD and, until recently, have been considered to be ‘undruggable’ for the past several decades ( 8 – 10 ).…”

Section: Introductionmentioning

confidence: 99%

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Resistance to KRAS inhibition in advanced non-small cell lung cancer

Sreter,

Catarata,

von Laffert

et al. 2024

Front. Oncol.

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Lung cancer remains the leading cause of cancer death globally. More than 50% of new cases are diagnosed in an advanced or metastatic stage, thus contributing to the poor survival of such patients. Mutations in the KRAS (Kirsten rat sarcoma virus) gene occur in nearly a third of lung adenocarcinoma and have for decades been deemed an ‘undruggable’ target. Yet, in recent years, a growing number of small molecules, such as the GTPase inhibitors, has been investigated in clinical trials of lung cancer patients harboring KRAS mutations, yielding promising results with improved outcomes. Currently, there are only two approved targeted therapies (adagrasib and sotorasib) for advanced or metastatic KRAS-mutated NSCLC from the second-line setting onwards. In this narrative review, we will focus on KRAS, its molecular basis, the role of its co-mutations, clinical evidence for its inhibition, putative mutation to resistance, and future strategies to overcome resistance to KRAS inhibition.

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Section: Clinical Evidence For Kras Inhibition In Kras ...mentioning

confidence: 99%

Section: Novel Direct Kras G12c Inhibitorsmentioning

confidence: 99%

Section: Mechanisms Of Resistance To Kras Inhibitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Resistance to KRAS inhibition in advanced non-small cell lung cancer

Sreter,

Catarata,

von Laffert

et al. 2024

Front. Oncol.

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“…Additionally, HH0043 exhibited a durable p-ERK inhibition in reference to the p-ERK modulation in tumors at 2 and 24 h, and this may be attributed to SOS1 inhibition, which could delay the ERKdependent negative feedback and, therefore, maintain longer p-ERK inhibition. 15 The synthetic route to prepare HH0043 as a representative compound is outlined in Scheme 1. Carboxylic acid (11) was converted to a Weinreb amide 12 and then treated with methyl magnesium bromide at 0 °C to afford ketone 13.…”

mentioning

confidence: 99%

Lead Identification of Novel Naphthyridine Derivatives as Potent SOS1 Inhibitors

Li,

Xie,

Yang

et al. 2024

ACS Med. Chem. Lett.

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SOS1, a guanine nucleotide exchange factor (GEF), plays a critical role in catalyzing the conversion of KRAS from its GDP- to GTP-bound form, regardless of KRAS mutation status, and represents a promising new drug target to treat all KRAS-driven tumors. Herein, we employed a scaffold hopping strategy to design, synthesize, and optimize a series of novel binary ring derivatives as SOS1 inhibitors. Among them, compound 10f (HH0043) displayed potent activities in both biochemical and cellular assays and favorable pharmacokinetic profiles. Oral administration of HH0043 resulted in a significant tumor inhibitory effect in a subcutaneous KRAS G12C-mutated NCI-H358 (human lung cancer cell line) xenograft mouse model, and the tumor inhibitory effect of HH0043 was superior to that of BI-3406 at the same dose (total growth inhibition, TGI: 76% vs 49%). On the basis of these results, HH0043, with a novel 1,7-naphthyridine scaffold that is distinct from currently reported SOS1 inhibitors, is nominated as the lead compound for this discovery project.

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Unraveling (K)RAS in pancreatic ductal adenocarcinoma

Doleschal

2024

memo

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SummaryPancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a poor 5‑year survival rate. The majority of PDAC cases harbor KRAS mutations, predominantly at codon 12, with G12D being the most common. While selective inhibitors like sotorasib have shown promise in KRASG12C-mutated PDAC, these mutations are rare, and resistance develops rapidly. Efforts to target more prevalent mutations like KRASG12D are ongoing, with compounds such as MRTX1133 showing preclinical efficacy. Resistance mechanisms include secondary mutations and pathway reactivation, prompting the development of pan-(K)RAS inhibitors (e.g., RMC-6236) and combination strategies targeting upstream effectors. Novel approaches, such as KRAS-targeted vaccines and T‑cell receptor (TCR) therapies, offer additional potential. Continued clinical trials are crucial to optimizing KRAS-targeted therapies in PDAC.

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Targeting KRAS in cancer

Cited by 33 publications

References 129 publications

Resistance to KRAS inhibition in advanced non-small cell lung cancer

Resistance to KRAS inhibition in advanced non-small cell lung cancer

Lead Identification of Novel Naphthyridine Derivatives as Potent SOS1 Inhibitors

Unraveling (K)RAS in pancreatic ductal adenocarcinoma

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