2. Academic Validation
  3. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity

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

  • Nature. 2019 Nov;575(7781):217-223. doi: 10.1038/s41586-019-1694-1.
Jude Canon 1,  Karen Rex  # 2,  Anne Y Saiki  # 2,  Christopher Mohr 2,  Keegan Cooke 2,  Dhanashri Bagal 3,  Kevin Gaida 2,  Tyler Holt 2,  Charles G Knutson 4,  Neelima Koppada 4,  Brian A Lanman 2,  Jonathan Werner 2,  Aaron S Rapaport 3,  Tisha San Miguel 2,  Roberto Ortiz 4 5,  Tao Osgood 2,  Ji-Rong Sun 2,  Xiaochun Zhu 4 6,  John D McCarter 2,  Laurie P Volak 4 7,  Brett E Houk 8,  Marwan G Fakih 9,  Bert H O'Neil 10,  Timothy J Price 11 12,  Gerald S Falchook 13,  Jayesh Desai 14,  James Kuo 15,  Ramaswamy Govindan 16,  David S Hong 17,  Wenjun Ouyang 3,  Haby Henary 8,  Tara Arvedson 3,  Victor J Cee 2,  J Russell Lipford 18
Affiliations

Affiliations

  • 1 Amgen Research, Amgen Inc, Thousand Oaks, CA, USA. jcanon@amgen.com.
  • 2 Amgen Research, Amgen Inc, Thousand Oaks, CA, USA.
  • 3 Amgen Research, Amgen Inc, South San Francisco, CA, USA.
  • 4 Amgen Research, Amgen Inc, Cambridge, MA, USA.
  • 5 Pfizer, La Jolla, CA, USA.
  • 6 Takeda, Cambridge, MA, USA.
  • 7 Celgene, San Diego, CA, USA.
  • 8 Amgen Clinical Development, Amgen Inc, Thousand Oaks, CA, USA.
  • 9 City of Hope, Duarte, CA, USA.
  • 10 Indiana University School of Medicine, Indianapolis, IN, USA.
  • 11 The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
  • 12 University of Adelaide, Adelaide, South Australia, Australia.
  • 13 Sarah Cannon Research Institute, Denver, CO, USA.
  • 14 Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
  • 15 Scientia Clinical Research, Randwick, New South Wales, Australia.
  • 16 Washington University School of Medicine, St Louis, MO, USA.
  • 17 The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 18 Amgen Research, Amgen Inc, Thousand Oaks, CA, USA. jlipford@amgen.com.
  • # Contributed equally.
PMID: 31666701 DOI: 10.1038/s41586-019-1694-1
Abstract

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 development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.

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