**4.1 KRAS**

KRAS is a member of the RAS family of proto-oncogenes, which also includes HRAS and NRAS. These three RAS genes encode monomeric GTPases that play a critical role in controlling the signal transduction pathways, regulate cell proliferation, differentiation, and cell survival. RAS proteins are bound to guanosine diphosphate (GDP) and are inactive in normal quiescent cells. On binding of the growth factor to the growth factor receptor, there is a transition to the active guanosine triphosphate (GTP) bound form that leads to the formation of an activated RAS-GTP complex, and this complex further bind to activate a number of other downstream signaling pathways such as RAF/MEK/MAPK/RAS PI3K/AKT pathways. Downstream signaling of pathways is initiated *via* KRAS incited by various growth factor receptors including EGFR and thus constitutive activation of this protein overcomes the need for growth

**Figure 1.** *Molecular pathogenesis of lung cancer.*

*Perspective Chapter: Molecular Pathology of Lung Cancer DOI: http://dx.doi.org/10.5772/intechopen.109598*

factor-mediated signaling. Activating RAS mutations alter the GTPase activity of the protein, thus hampering the inactivation of active RAS-GTP to GDP which leads to an increase in the downstream growth-promoting signaling pathway. In lung cancer, RAS/RAF/MEK/MAPK signal transduction cascade plays a pivotal role (**Figure 2**).

Activating KRAS mutation is the commonest oncogenic alteration in lung adenocarcinoma, which occurs in about 25–40% of cases, while mutations of HRAS and NRAS are very rare. KRAS mutation is more frequently observed in males and smokers. A total of 0–15% cases of adenocarcinoma in never smokers reported KRAS mutation. In squamous cell carcinoma or small-cell carcinoma, KRAS mutation is very rare or absent. KRAS mutations primarily occur at codon 12, occasionally at codon 13, and very rare at codon 61. The most common mutations in KRAS are G to T transversions (~84%) in smokers, while never smokers have G to A transitions.

EGFR and KRAS mutations are mutually exclusive, although there may be rare exceptions to this. A literature review has suggested that KRAS mutant tumors are resistant to the EGFR tyrosine kinase inhibitors (TKIs), as the mutations in KRAS lead to constitutive activation of the pathways, which are downstream of EGFR. In lung cancer, the high frequency of KRAS mutations makes it an ideal target for the treatment of cancer [14–23].

#### **4.2 EGFR**

EGFR is a member of erbB family having closely related receptor tyrosine kinases, which also includes erbB1 (also known as EGFR), erbB2 (HER2), erbB3, and erbB4. EGFR has an extracellular ligand binding domain, a transmembrane portion, and intracellular tyrosine kinase and regulatory domains. On binding of a specific ligand (e.g., epidermal growth factor), there occurs a conformational change and phosphorylation of the intracellular domain occurs, which leads to downstream signal transduction by various pathways that include PI3K/AKT/mTOR, RAS/RAF//MAPK, and JAK/STAT signaling pathways. Depending on the pathway undertaken, the end result is cell proliferation or cell maintenance by inhibition of apoptosis (**Figure 3**).

#### **Figure 3.** *EGFR signal transduction in cancer cells.*

DNA mutations in EGFR can occur in the extracellular region or intracellular portions of the protein. In 43–89% cases of non-small-cell lung cancer, overexpression of EGFR or mutations in intracellular EGFR have been observed. Mutations in the EGFR tyrosine kinase domain are observed in around one-quarter of NSCLC and are associated with increased receptor expression in 75% of cases. Exon 19 frame deletions and exon 21 point mutation are the most common domain mutations in EGFR tyrosine kinase leading to the substitution of leucine at codon 858 in place of arginine, as a result of which signal transduction pathways get activated resulting in increased proliferation of cells and inhibition of apoptosis irrespective of the presence of ligand at extracellular site. Mutations in exons 18 and 21 are less commonly observed.

All EGFR mutations are observed in adenocarcinoma of the lung, although they can also be seen in adenosquamous carcinomas. EGFR mutations are more commonly observed in young female patients with no history of smoking but there can be exceptions to this. EGFR mutations are very rarely observed in pure squamous cell carcinoma of the lung. In patients who develop resistance to EGFR TKIs, secondary mutations in EGFR are observed, the commonest is the T790M activating point mutation in exon 20 [17, 18, 24–29].
