Exploiting the therapeutic implications of KRAS inhibition on tumor immunity

Molina-Arcas, Miriam; Downward, Julian

doi:10.1016/j.ccell.2024.02.012

Cited by 26 publications

(10 citation statements)

References 161 publications

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“…Oncogenic mutations for all isoforms are particularly common in residues 12, 13 and 61 and result in an increase in the rate of GDP-GTP exchange. Although the oncogenic potential of RAS has been known since the early 1980s along with the mutations, it has proved "undruggable" for many years with the first bona fide RAS inhibitors being approved for emergency clinical use over 30 years later in 2022 [27]. These (sotorasib, adagrasib) target the third most commonly mutated form, KRAS(G12C), and are highly specific, utilising the cysteine residue in the GDP-bound (inactive) form for covalent modification, locking the protein in an inactive conformation.…”

Section: Oncogenic Potential Of the Erk1/2 Cascade And Development Of...mentioning

confidence: 99%

See 1 more Smart Citation

Inhibiting the Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Cascade in Cancer and the Heart: for Better or Worse, in Sickness and Health?

Clerk

2024

IJDDP

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Review Inhibiting the Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Cascade in Cancer and the Heart: for Better or Worse, in Sickness and Health? Angela Clerk *, Shona U Amadi, Samuel J Smith, and Peter H Sugden School of Biological Sciences, University of Reading, Reading RG6 6AS, UK * Correspondence: a.clerk@reading.ac.uk Received: 3 April 2024; Revised: 27 April 2024; Accepted: 29 April 2024; Published: 23 May 2024 Abstract: The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are the prototypic mitogen-activated protein kinases, first discovered and investigated in the context of cell division and their role in cancer. ERK1/2 are phosphorylated and activated by upstream kinases, MEK1/2 (also known as MKK1/2) that are in turn phosphorylated and activated by RAF kinases (RAF1, BRAF, ARAF), these being activated by small G proteins of the RAS family (HRAS, KRAS, NRAS). The oncogenic nature of the pathway has resulted in the generation of highly specific inhibitors that are successfully used to treat cancer, particularly melanoma. Those in clinical use currently inhibit some isoforms of RAS, RAF kinases and MEK1/2, with additional inhibitors of these kinases in clinical trials. New drugs are now entering the clinic to inhibit ERK1/2 themselves. The ERK1/2 cascade is also important in the heart. It promotes cardiomyocyte hypertrophy and cardioprotection to counter pathophysiological stresses, and plays a significant role in enhancing cardiac fibrosis with detrimental consequences for cardiac function. Here, we summarise the role of ERK1/2 signalling in cancer and the heart, we outline the development of ERK1/2 cascade inhibitors for cancer providing information on those that are approved as cancer treatments and those which are in clinical trials, and we discuss the known and predicted consequences of these ERK1/2 cascade inhibitors for the heart. Integral with this, we consider whether these drugs are necessarily detrimental to the heart or if/when they may be repurposed to prevent or treat heart failure.

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Section: Oncogenic Potential Of the Erk1/2 Cascade And Development Of...mentioning

confidence: 99%

“…The greatest advance is the development of RAS inhibitors (Table 2; Supplementary Table S2). These are largely targeted to mutated forms of RAS, and most are covalent inhibitors targeting the cysteine residue of KRAS (G12C) for modification [27]. As such, they appear very specific.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Inhibiting the Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Cascade in Cancer and the Heart: for Better or Worse, in Sickness and Health?

Clerk

2024

IJDDP

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“…Remarkably, due to milestone achievements in recent years, the field has now been inundated with KRAS inhibitors, some which are discussed below. In addition to the two KRAS G12C inhibitors that have been granted accelerated approval, there are at least 17 additional KRAS G12C inhibitors, 5 KRAS G12D inhibitors, and 3 RAS inhibitors targeting multiple mutations undergoing clinical evaluation (88). Many more KRAS inhibitors are in the IND-enabling phase or in preclinical development.…”

Section: Direct Inhibitors Of Krasmentioning

confidence: 99%

Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment

Long,

Amparo,

Goodhart

et al. 2024

Front. Oncol.

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Despite significant advancements in the treatment of other cancers, pancreatic ductal adenocarcinoma (PDAC) remains one of the world’s deadliest cancers. More than 90% of PDAC patients harbor a Kirsten rat sarcoma (KRAS) gene mutation. Although the clinical potential of anti-KRAS therapies has long been realized, all initial efforts to target KRAS were unsuccessful. However, with the recent development of a new generation of KRAS-targeting drugs, multiple KRAS-targeted treatment options for patients with PDAC have entered clinical trials. In this review, we provide an overview of current standard of care treatment, describe RAS signaling and the relevance of KRAS mutations, and discuss RAS isoform- and mutation-specific differences. We also evaluate the clinical efficacy and safety of mutation-selective and multi-selective inhibitors, in the context of PDAC. We then provide a comparison of clinically relevant KRAS inhibitors to second-line PDAC treatment options. Finally, we discuss putative resistance mechanisms that may limit the clinical effectiveness of KRAS-targeted therapies and provide a brief overview of promising therapeutic approaches in development that are focused on mitigating these resistance mechanisms.

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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%

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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Exploiting the therapeutic implications of KRAS inhibition on tumor immunity

Cited by 26 publications

References 161 publications

Inhibiting the Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Cascade in Cancer and the Heart: for Better or Worse, in Sickness and Health?

Inhibiting the Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Cascade in Cancer and the Heart: for Better or Worse, in Sickness and Health?

Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment

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

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