Cetuximab KRAS Testing

Cetuximab KRAS Testing

The Food and Drug Administration has approved a new cetuximab indication in colorectal cancer along with a genetic test to rule out patients who carry a KRAS mutation and therefore would not benefit from treatment.Jul 9, 2012

How is KRAS mutation detected?

Three of the commonly used methods for KRAS mutation detection in clinical samples, include nucleic acid sequencing (dideoxy and pyrosequencing), real-time PCR with meltcurve analysis and allele-specific PCR with various modes used to distinguish mutant from wild-type sequences.

What does KRAS positive mean?

KRAS-positive lung cancer, refers to any lung cancer that tests positive for a KRAS biomarker. The KRAS biomarker is present in approximately 15-25% of patients with non-small cell lung cancer (NSCLC). The KRAS biomarker belongs to a class of genes known as oncogenes.

How do you treat KRAS mutation?

Standard first-line therapy for a patient with KRAS positive lung cancer may be surgery, radiation, chemotherapy, immunotherapy or a combination based on the stage of their cancer. There is now a targeted therapy pill (also called a KRAS inhibitor) for patients with KRAS G12C.

What does KRAS mean in medical terms?

KRAS (Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell’s nucleus.

Is KRAS mutation treatable?

KRAS mutations are the most common oncogenic alteration in all of human cancers and there are currently no effective treatments available for patients with KRAS-mutant cancers.

What does BRAF stand for?

BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf.

What is KRAS G12C mutation?

G12C is a single point mutation with a glycine-to-cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis.

Is KRAS a tumor suppressor gene?

KRAS oncogene and Carcinogenesis as a multistep process

Alterations in oncogenes, tumor-suppressor genes, and micro-RNA genes are important in pathogenesis of cancer (2). These alterations are a sequential multistep process that in the end results in neoplastic transformation.

Is KRAS the same as Ras?

The KRAS gene is in the Ras family of oncogenes, which also includes two other genes: HRAS and NRAS. These proteins play important roles in cell division, cell differentiation, and the self-destruction of cells (apoptosis).

Is KRAS a biomarker?

Take home message: KRAS has been recognized as an outstanding predictive biomarker to select mCRC and NSCLC patients for EGFR-targeted therapies; however, multi-determinant approaches including other molecular markers should facilitate the identification of patients likely to respond to such therapies.

Why is KRAS Undruggable?

For more than 30 years after its discovery, KRAS was considered undruggable target due to the intrinsic characteristics of KRAS proteins. The KRAS is small and has a considerably smooth and shallow surface, resulting in difficulty of small molecule binding to the KRAS.

Are BRAF and KRAS mutually exclusive?

Oncogenic activation of KRAS and BRAF is mutually exclusive and occurs in approximately 40% and 10% of all CRCs, respectively.

How common are KRAS mutations?

1. Three most common KRAS mutations were G12C (32.1%), G12D (23.4%) and G12V (21.1%). Other codon 12 mutations including G12A (12.8%), G12S (4.1%) and G12R (1.4%) were found in 20% of the patients.

What happens when mutated KRAS?

Mutated (changed) forms of the KRAS gene have been found in some types of cancer, including non-small cell lung cancer, colorectal cancer, and pancreatic cancer. These changes may cause cancer cells to grow and spread in the body.

Is KRAS mutation genetic?

The KRAS-variant is an inherited genetic mutation associated with a family history of cancer, especially breast,1 ovarian,2 lung,3 as well as other cancers,4,5 and multiple cancers in the same individual.

What type of protein is KRAS?

1. Introduction. GTPase KRas (KRAS) is a signal transducer protein, which plays an important role in various cellular signalling events such as in regulation of cell proliferation.

What is KRAS negative?

The KRAS gene, which has been extensively studied for more than three decades, has been demonstrated to be a strong negative predictive biomarker to indicate whether a CRC patient will respond to anti-EGFR treatment.

Why is KRAS Hard Target?

Specific KRAS inhibition has been difficult to accomplish due to the small size of the protein and a surface area with few deep pockets for drug interaction, but numerous agents under investigation in preclinical and clinical models have overcome this challenge by using the distinct alterations of KRAS mutant tumors to …

What are KRAS mutated cancers?

KRAS mutations are present in approximately 25% of tumors, making them one of the most common gene mutations linked to cancer. They are frequent drivers in lung, colorectal and pancreatic cancers. KRAS drives 32% of lung cancers, 40% of colorectal cancers, and 85% to 90% of pancreatic cancer cases.

How do KRAS inhibitors work?

Drugs that target cells with KRAS gene changes

NSCLCs with this mutation are often resistant to other targeted drugs such as EGFR inhibitors (see below). Sotorasib (Lumakras) is a type of drug known as a KRAS inhibitor. It works by attaching to the KRAS G12C protein, which keeps the cancer cell from growing.

What cancers have BRAF mutations?

BRAF mutation is seen in melanoma, papillary thyroid carcinoma (including papillary thyroid carcinoma arising from ovarian teratoma), ovarian serous tumours, colorectal carcinoma, gliomas, hepatobiliary carcinomas and hairy cell leukaemia.

Is it better to be BRAF positive or negative?

We have demonstrated that BRAF positive patients receiving targeted treatment have significantly better survival than their BRAF negative counterparts.

What are BRAF driven cancers?

These cancers include: Melanoma (about half of all melanomas have the BRAF gene mutation) Hairy cell leukemia. Non-Hodgkin lymphoma.

How common is KRAS G12C?

The KRAS G12C mutation occurs in about 13% of NSCLC patients, and 1%-3% of colorectal and other solid tumors. G12C is a single point mutation with a glycine-to-cysteine substitution at codon 12.

Is sotorasib and immunotherapy?

Sotorasib is now a great treatment option for these patients after disease progression on front-line chemotherapy and immunotherapy, said Dr. Velcheti.

What is KRAS inhibitor?

The CodeBreaK100 trial, funded by Amgen and NCI, is testing sotorasib (previously called AMG510) as a treatment for people with solid tumors that have KRAS G12C. The mutation, a hallmark of damage from cigarette smoke, is most common in lung cancer.

What is Lynch syndrome?

Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is the most common cause of hereditary colorectal (colon) cancer. People with Lynch syndrome are more likely to get colorectal cancer and other cancers, and at a younger age (before 50), including.

When was KRAS mutation discovered?

In 1982-3, orthologs of viral ras oncogenes with point mutations were identified in transforming DNA fragments from human cancer cells both for HRAS [2631] and KRAS [3234].

How many amino acids are in KRAS?

Human KRAS has two isoforms. The prediminant isoform (b) is the 188 amino acid protein (NP_004976), isoform a is 189 amino acids long.

Description: Crystal Structure of small molecule ARS-1620 covalently bound to K-Ras G12C.
References: 9

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What is the difference between KRAS and HRAS?

Mutant Hras drives lung tumorigenesis

The Kras 4A isoform shares with Hras and Nras a post-translational modification that includes covalent attachment of a palmitoyl moiety, whereas the modification of the predominant Kras 4B is limited to farnesylation or geranylgeranylation6.

Does KRAS contribute to apoptosis?

Oncogenic KRAS mutations contribute to apoptosis resistance and treatment failure. We observed the novel finding of significant upregulation of anti-apoptotic Bcl-xL expression in KRAS mutant compared to wild-type cells that was regulated by ERK downstream of KRAS.

What is the difference between NRAS HRAS and KRAS?

For example, KRAS mutations are found in nearly 90% of pancreatic cancers. In myeloid malignancies, NRAS mutations are more frequent than KRAS mutations, whereas HRAS mutations are rare. The mechanism underlying the different frequencies of RAS isoforms mutated in myeloid malignancies is not known.

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