The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity

  title={The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity},
  author={Jude Canon and Karen L. Rex and Anne Y Saiki and Christopher Mohr and Keegan S. Cooke and Dhanashri Bagal and Kevin Gaida and Tyler Holt and Charles G. Knutson and Neelima Koppada and Brian A. Lanman and Jonathan Werner and Aaron S. Rapaport and Tisha San Miguel and Roberto Ortiz and Tao Osgood and Ji-rong Sun and Xiaochun Zhu and John D. McCarter and Laurie P. Volak and Brett E. Houk and Marwan G Fakih and Bert H O'Neil and Timothy Jay Price and Gerald S Falchook and Jayesh Desai and James C. Kuo and Ramaswamy Govindan and David S. Hong and Wenjun Ouyang and Haby Adel Henary and Tara Arvedson and Victor J. Cee and James Russell Lipford},
KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3–5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical… 

Two new agents target KRAS G12C

  • Diana Romero
  • Medicine, Biology
    Nature Reviews Clinical Oncology
  • 2019
MRTX849 and AMG 510 are currently being tested in firstinhuman clinical trials involving patients with KRASG12Cmutant solid tumours, mostly nonsmall-cell lung carcinoma (NSCLC) or colorectal carcinoma, and their toxicities, and mechanisms of resistance, are eagerly awaited.

Cytotoxic activity of KRAS inhibitors in combination with chemotherapeutics

This review describes the KRAS G12C mutation-specific inhibitors and the SOS1-targeting inhibitors that reduce the GTP- loading of wildtype and mutated KRAS.

Targeting KRAS: Crossroads of Signaling and Immune Inhibition

The clinical characteristics of cancer with KRAS mutation; successful development of the KRAS G12C inhibitor and its impact on the tumor immune microenvironment; and potential new avenues such as the combination strategy using KRAS inhibitor and ICI to improve therapeutic efficacy for patients with cancer harboring KRAS mutations are described.

Therapeutic KRASG12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers

KRAS inhibition mobilizes anti-tumour immunity in immunogenic lung cancer models through derepressing interferon signaling via repression of Myc, with implications for the design of clinical trials combining KRASG12C inhibitors with anti-PD1 drugs.

KRAS G12C Mutations in NSCLC: From Target to Resistance

The biology of KRAS G12C, mechanisms of drug resistance and potential approaches to overcome the later are reviewed, with a specific focus on primary and secondary resistance mechanisms and their possible clinical implications.

KRAS: A Druggable Target in Colon Cancer Patients

Attempts to obtain mutant-specific KRAS (KRASG12C) switch-II covalent inhibitors are ongoing and the results are promising, giving the possibility to assess the best therapeutic approach to KRAS-driven tumors.

Targeting KRASG12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments

Patients with colorectal cancer derive less benefit compared to those with non-small cell lung cancer (NSCLC), likely due to rapid treatment-induced resistance through increased epidermal growth factor receptor (EGFR) signaling, and combination therapy trials with EGFR inhibitors are currently underway.

Targeting Mutated KRAS Genes to Treat Solid Tumours.

The importance of mutant KRAS in solid tumours, prior attempts at inhibiting mutantKRAS, and the current promising targeted agents being investigated in clinical trials are summarized, along with future challenges.

Resistance to KRASG12C Inhibitors in Non-Small Cell Lung Cancer

This review focuses on the intrinsic and acquired mechanisms of resistance to KRASG12C inhibitors in KRASg12C mutant non-small cell lung cancer and the potential clinical strategies to overcome or prevent it.

KRASG12C inhibitor: combing for combination.

An update on combination opportunities which could be explored to maximize the benefit of this new exciting drug, G12Ci, which is being explored to tackle KRAS mutant cancer.



Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State.

ARS-853 is described, a selective, covalent inhibitor of KRAS(G12C) that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation.

The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors

Kinetic and structural analyses show that the activity of two covalent inhibitors of human KRASG12C, which initially bind to a shallow pocket with low affinity, is driven by KRAS-mediated catalysis of the chemical reaction with Cys12.

KRAS Mutations and Susceptibility to Cetuximab and Panitumumab in Colorectal Cancer

Clinical data is reviewed and the implications for future drug development in colorectal cancer are discussed, including the economic and ethical considerations involved in the development of novel targeted therapies.

Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer

The safety profile of the anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of mCRC is reviewed.

Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology

In vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays, and dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies.

The Combination of MEK Inhibitor With Immunomodulatory Antibodies Targeting Programmed Death 1 and Programmed Death Ligand 1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer.

  • J. W. LeeYu Zhang J. Koo
  • Biology, Medicine
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
  • 2019

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

Characterization of murine syngeneic tumor models highlighted the importance of extensive profiling and will enable investigators to select appropriate models to interrogate the activity of immunotherapies as well as combinations with targeted therapies in vivo.

Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma

The most common and serious adverse events associated with BRAF targeted agents are reviewed and management algorithms to guide practitioners in using these drugs effectively in the clinic are suggested.