The KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) DNA sequence falls into the classification of genes which when subject to specific mutations, contributes to the cancerous nature of the affected cell (proto-oncogenes) [1]. Over the past three decades proto-oncogenes have been the focus for targeted cancer therapies to great success. However, a clinically approved targeted therapy directed against KRAS mutated tumours has as of yet, remained elusive; in a recent paper published in Nature, Canon, J. et al [2] have aggregated substantial pre-clinical evidence of anti-tumour activity when using the oral inhibitor (of KRAS G12C), AMG 510. This may be the first steps towards a novel treatment for tumours with the specific KRAS G12C mutations.

KRAS genes are a sub-category of RAS proto-oncogenes which are active mutations in ~30% of all cancers [1]. The KRAS G12C gene mutation affects approximately ~10.9% of lung cancer patients and between ~2.5% and ~5.1% of colorectal cancer patients [3] (estimates vary based on testing methodology and histopathology). Lung cancer patients with KRAS mutations have the highest frequency of G12C mutated KRAS proteins of the four human cancers with the highest rates of KRAS mutations (see fig 1) [4].


The GTPase-activating KRAS proteins encoded for by KRAS genes play a vital role in cell signalling pathways which regulate cell growth and division; KRAS protein activations is regulated by the binding of either a GDP (Guanosine diphosphate, inactive form) or GTP (guanosine triphosphate, active form) molecule. GDP and GTP binding to a KRAS protein is catalysed by GEP (guanine nucleotide exchange factors, activates KRAS) and GAP (GTPase-accelerating proteins, inactivates KRAS) (see fig 2).


Prolonged activation of KRAS proteins causes a cell signalling cascade which promotes cell division/growth and inhibits cell apoptosis. contributing to the malignancy of cancer cells. A KRAS G12C mutated gene produce KRAS proteins with glycine 12 mutations (substituted for cysteine) which inhibit the binding of GAP to its binding pocket within the G-domain of the KRAS protein [1].  The inhibition of G12C KRAS proteins via AMG 510 covalently binding to the missense mutated cysteine base, create an AMG 519-KRAS(G12C) complex which is an inactive form of the KRAS protein [2].

Still in the early phase I/II of clinical trials [5], this eagerly anticipated KRAS inhibitor has the potential to gain a large market share of lung cancer treatment revenues and create substantial growth by improving treatment outcomes.   


[1] Lie, P. et al. Targeting the untargetable KRAS in cancer therapy. Acta Pharmaceutica Sinica; 9(5); 871-879. 2019

[2] Canon, J. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature; 575; 217–223. 2019

[3] Accessed: Accessed: 12/1/2019 at 11:45am GMT

[4] Vasan, N. et al. A  RAS renaissance:Emerging targeted therapies for KRAS-mutated non-small cell lung cancer. Clin Cancer Res; 20(15); 3921–30. 2014

[5] Accessed: 12/1/2019 at 11:37am GMT (NCT03600883)