Lung Cancer- NRAS Mutation Panel

NRAS overview:
  • The RAS genes are highly homologous but functionally distinct[1]
  • RAS proteins are central mediators that downstream the growth factor receptor signaling and are critical for cell proliferation, survival, and differentiation.
  • RAS can activate several downstream effectors, including the PI3K-AKT-mTOR pathway, which is involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation.
  • Activating mutations within the RAS gene result in constitutive activation of the RAS GTPase, even in the absence of growth factor signaling which results in sustained proliferation signal within the cell.
  • Specific RAS genes are recurrently mutated in different malignancies. RAS mutations are particularly common in colon cancer, lung cancer, and pancreatic cancer[2]
 NRAS mutation in Lung Cancer:
  • NRAS are closely related RAS oncogene family members, and mutations in genes either at codons 12, 13 (exon 2), codon 61 (exon 3) and codon 146 (exon 4) result in overactive RAS signalling which promotes oncogenesis.
  • NRAS mutations are more commonly found in lung cancers with a history of smoking[3].
  • Majority of cases, NRAS mutations are missense mutations that introduce an amino acid substitution at position 61.
  • The result of these mutations is constitutive activation of NRAS signaling pathways.
  • NRAS mutations are non-overlapping with other oncogenic mutations found in NSCLC
NRAS mutation and risk factors in Lung Cancer:
  • RAS mutations are detected in 15–20% of NSCLC and, particularly, 30–50% of adenocarcinomas (ADC) [3].
  • In lung cancer, 90% of the mutations are located in the RAS2 gene and both NRAS mutations and HRAS mutations have been occasionally documented [4].
  • Somatic mutations in NRAS have been found in ~1% of all NSCLC [5&6].
  • Currently, there are no direct anti-NRAS therapies available, but preclinical models suggest that MEK inhibitors may be effective.
  • NRAS mutations have been associated with sensitivity to MEK1/2 inhibitors in preclinical studies[5].
  • NRAS mutations, have been associated with decreased sensitivity to EGFR TKIs treatment.
  • These mutations impair the intrinsic GTPase activity of RAS and confer resistance to GTPase activators, thereby causing RAS to accumulate in its active GTP-bound state, which sustains the activation of RAS signaling[7]
Reference:
  1. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. (2011). Nat Rev Cancer, 13:(11):761-74.
  2. Karnoub AE and Weinberg RA. (2008). Nat Rev Mol Cell Biol, 9(7):517-31.
  3. Rodenhuis S, Slebos RJ, Boot AJ, et al, (1988). Cancer Res, 48: 5738-5741
  4. Rodenhuis S, & Slebos RJ, (1990). Am Rev Respir Dis, 142: S27-S30
  5. Ohashi K, Sequist LV, Arcila ME, et al, (2013). Clin Cancer Res, 1;19(9):2584-91
  6. Ding L, Getz G, Wheeler DA, et al, (2008). Nature, 23;455(7216):1069-75.
  7. Trahey M & McCormick FA (1987). Science, 238:542-5