Detection and quantitative assessment of activating mutations in genes that control the effectiveness of targeted therapies
KRAS , is a protein that in humans is encoded by the KRAS gene. Μutation of a KRAS gene is an essential step in the development of many cancers. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. Somatic KRAS mutations are found at high rates in Leukemias, colon cancer , pancreatic cancer and lung cancer. Presence of the wild-type (or normal) KRAS gene does not guarantee that drugs will work effectively. A number of large studies have shown that cetuximab has significant efficacy in mCRC patients with KRAS wild-type tumors. EGFR positive patients have an impressive 60% response rate to Tarceva. However, KRAS positivity and EGFR positivity are generally mutually exclusive. Lung cancer patients who are KRAS positive have a low response rate to Tarceva estimated at 5% or less. In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.
The wild-type KRAS status might identify patients with metastatic colorectal cancer who are likely to respond to cetuximab and to have a longer overall survival. Cetuximab should not be proposed to ∼40% of all metastatic colorectal cancer patients having KRAS-mutated tumor cells. The presence of a KRAS mutation in EGFR-positive colorectal cancers might partially explain why one part of these tumors does not respond to cetuximab. K-ras is a G protein that plays a key role in the Ras/MAPK signaling pathway located downstream of many growth factor receptors, including EGFR, and involved in colorectal carcinogenesis. The recruitment of K-ras by the activated EGFR is responsible for the activation of a cascade of serine-threonine kinases from the cell surface to the nucleus. The Ras/MAPK pathway is one of the most important pathways for cell proliferation by inducing the synthesis of cyclin D1 and mutation of the KRAS proto-oncogene, which are found in 36% of colorectal cancers, leading to the activation of this pathway. Consequently, whatever the expression level of EGFR is, the presence of a KRAS mutation is associated with a downstream activation of the Ras/MAPK pathway, leading to cell proliferation that cannot be significantly inhibited by cetuximab that acts upstream of the K-ras protein. KRAS mutation is associated with resistance to cetuximab and a shorter survival in EGFR-positive metastatic colorectal cancer patients treated with this therapy. Thus, KRAS mutation status might allow the identification of patients who are likely to benefit from cetuximab and avoid a costly and potentially toxic administration of this treatment in nonresponder patients.
BRAF is a human gene that makes a protein called B-Raf. The B-Raf protein is involved in sending signals inside cells, which are involved in directing cell growth . Certain other inherited BRAF mutations cause birth defects. Drugs that treat cancers driven by BRAF have been developed. Mutations in the BRAF gene can cause disease in two ways. First, mutations can be inherited and cause birth defects. Second, mutations can appear later in life and cause cancer, as an oncogene. Acquired mutations in this gene have been found in cancers, including non-Hodgkin lymphoma , colorectal cancer , malignant melanoma , papillary thyroid carcinoma , non-small cell lung carcinoma , and adenocarcinoma of lung . The V600E mutation of the BRAF gene has been associated with Hairy Cell Leukemia in numerous studies. More than 30 mutations of the BRAF gene associated with human cancers have been identified. The frequency of BRAF mutations varies widely in human cancers from more than 80% in melanomas and nevi , to as little as 0-18% in other tumors , such as 1-3% in lung cancers and 5% in colorectal cancer.
Phosphatidylinositol 3-kinases (PI 3-kinases or PI3Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. PI 3-kinases have been linked to an extraordinarily diverse group of cellular functions, including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. PI 3-kinases are also a key component of the insulin signaling pathway. Hence there is great interest in the role of PI 3-kinase signaling in Diabetes mellitus. The class IA PI 3-kinase p110α is mutated in many cancers. Many of these mutations cause the kinase to be more active. Hence, PI 3-kinase activity contributes significantly to cellular transformation and the development of cancer.