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

@article{Canon2019TheCK,
  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},
  journal={Nature},
  year={2019},
  volume={575},
  pages={217-223}
}
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
TLDR
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

TLDR
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

TLDR
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

TLDR
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

TLDR
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

TLDR
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

TLDR
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.

TLDR
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

TLDR
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.

TLDR
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.
...

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