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KRAS gene

G12A gene which is the human homolog of the Kirsten rat sarcoma-2 virus oncogene.

Kirsten-Ras (KRAS)

A membrane associated guanosine triphosphatase.

A proto-oncogene- located on chromosome 12, and encodes intracellular membrane bound RAS protein.

The RAS guanisine triphosphate complex activates signaling pathways such as , or Raf/MEK/ERK & PI3K/AKT/mammalian targeted rapamycin, which play key roles in cell proliferation, differentiation, and survival.

The most frequently mutated oncogene in human cancers.

KRAS accounts for 85% of RAS mutations observed in human cancers.

KRAS mutations are mostly missense mutations leading  to permanent and constitute of activation of the RAS oncoprotein, promoting tumorigenesis.

The most common codon 12 mutation sub type is G 12 C.

KRAS mutations occur in approximately 25% of non-small cell lung cancers, approximately 40% of adenocarcinomas and 0.5 to 4% of squamous lung cancers.

KRAS  mutated non-small cell lung cancers are generally associated with smoking, current or former, increased program death ligand-1 expression on tumors, increased tumor mutational burden, and increased tumor infiltrating lymphocyte count.

K or a S driven NSCLC is frequently associated with a history of smoking, high tumor, mutational burden, and genomics signatures of tobacco smoke exposure.

This mutation occurs in 3-4% of colorectal cancers and in 1 to 2% of biliary and pancreatic cancers.

The KRAS G12C mutation occurs in codon 12 and results in the substitution of a glycine with cysteine.

The KRAS G12C mutation is induced by smoking and is responsible for about 12% of lung adenocarcinomas.

The KRASG 12 C proteins keeps KRAS in the active bound state and drives oncogenenic signaling through multiple down stream pathways: They promote tumor cells, survival, proliferation, and metastasis.

KRAS G12C mutation occurs in approximately 3 to 4% of patients with metastatic colorectal cancer.

In a phase 3 trial of KRAS G12 C inhibitor Sotorasib plus Panitumumab an EGFR inhibitor in patients with refractory colorectal metastatic cancer improved survival vs standard treatment.

Encodes a GTP-binding protein that functions as a self-activating signal transducer by cycling GDP to GTP bound states.

Encodes guanosine triphosphatase bound states to regulate signal transduction.

KRAS medications are often associated with resistance to target therapies and poor outcomes in patients with cancer.

KRAS can be activated by extracellular stimuli and initiate downstream signaling pathways responsible for fundamental cell processes.

Stimulated by the epidermal growth factor receptor (EGFR) and other cell surface receptors.

The KRAS gene is essential for cell division because it sends signals to a biological on/off switch that tells cells went to start and stop dividing.

When mutated it creates a misshapen protein that prevents the switch from turning off and the cells never stop the dividing, forming a tumor.

Mutant KRAS  cells have decreased major histocompatibility class 1 expression, upregulation of programmed cell death-ligand 1, and promotion of immuno suppressive immune cell populations in the tumor microenvironment.

Mutant KRAS  cells enhance recruitment, accumulation, and maintenance of my Lloyd derive suppresses cells to the tumor microenvironment.

The above changes suggest that these alterations occur early in the carcinogenesis process and promote cancer cell survival, invasion, and migration.

Downstream effect to pathways of oncogenicgenic KRAS include mitogenic protein kinase (MAPK) come phosphatidylinoitol 3 kinase (PI3K, and RAS-like GEF, all the factors are responsible for cell proliferation, cell cycle regulation, metabolic changes, cell survival, and cell differentiation.

KRAS dysregulation lead to tumor growth by controlling interactions between cancer cells and the micro environment, affecting therapeutic response.

KRAS mutations are prevalent in common malignancies, such as lung and colorectal cancer.

The three Human Cancer types with the highest rate of KRAS mutations are: pancreatic (88%), colorectal (45–50%), and lung cancer (31–35%).

KRAS  G12C mutation occurs in approximately 13% of adeno lung cancers,  are in 1-3% of colorectal cancers and solid cancers.
KRAS G12 mutations occur in approximately 1 to 2% of pancreatic cancers.
The G12D single amino acid mutation of the KRAS family is the most frequent KRAS mutation and occurs in 41% of patients with pancreatic cancer.

KRAS G12 mutation is associated with poor prognosis compared to other KRAS mutations as well as KRAS wild type tumors.

The glycine-to-cysteine mutation at position 12 favors the active form of the KRAS  protein, resulting in a predominantly GTP-bound  KRAS onco-proteins and enhanced proliferation and survival in tumor cells.

The most common variants of the KRAS 12 codon mutation include V, D, and C.

KRAS G12C mutation is noted in lung cancer and colon rectal cancers and less frequently endometrial, pancreatic, and ovarian cancers.

As many as 5% of patients with colorectal cancer have the KRAS G12C mutation.

KRAS mutations occur in nearly 40% of patients with lung cancer, and among patients with colorectal cancer, as many as 5% have a KRAS p. G12C mutation.

G12C mutation Is more common in women.

KRAS mutations are observed in up to 30% of patients with NSCLC and occur primarily at codons 12 and 13.

KRAS gene-small G protein downstream of EGFR can acquire mutations in exon 2 and can isolate the EGFR pathway and make EGFR inhibitor ineffective.

Ras gene family consists of H-Ras, N-Ras and K-Ras.

The Ras proteins are usually small triphosphate binding proteinsof several signaling pathways that play key roles in signal transduction resulting in cellular proliferation and transformation.

Right-sided colorectal cancers have a high likelihood to have a KRAS mutation.

Mutations associated with poor response to epithelial growth factor inhibitor treatment in colorectal cancer.

KRAS mutations are prevalent in solid tumor cancerous, and about 40-50% of colon cancer have a mutation in RAS pathway which includes the KRAS, NRAS, and BRAF genes.

RAS pathway mutations solid tumors less likely to respond to current therapies.

Patients with KRAS mutations in exon 2 do not have a response to anti-EGFR therapy and they have inferior outcomes if this therapy is combined with oxaliplatin containing chemotherapy regimens.

Absence of gene mutations associated with favorable outcomes with the use of epithelial growth factor inhibitors cetuximab (Erbitux) and panitumumab (Vectibix).

Patients with metastatic colon cancer with KRAS codon 12-or 13-mutated tumors are presently excluded from treatment with anti-epidermal growth factor receptor monoclonal antibody treatments.

KRAS mutations are usually mutually exclusive with other talkable congenic drivers such as EGF or or ALK mutations.

KRAS G12 C is the most common variant accounting for nearly 40% of all KRAS mutations – 12 NSCLC‘s.

It is the KRAS mutation status that is the most important predictor for the lack of benefit from anti-EGFR therapy.

In a study of 89 patients with colon cancer treated with cetuximab, after failure of irinotecan based regimens, KRAS mutations at codon 12/13 were identified in 27% of patients with a treatment response of 0%, while treatment response was 40% in patients without KRAS mutations, the median progression free survival was 10 weeks versus 31.4 weeks and overall survival 10.1 months versus 14.3 months, respectively (Lievre).

CO 17 study a randomized trial showed that among colorectal cancer patients that failed chemotherapy, monotherapy with cetuximab improved overall survival and progression free survival than did supportive care.

The addition of cetuximab to FOLFIRI chemotherapy as first-line therapy in metastatic colon cancer improves survival in patients with KRAS wild type disease (Van Cutsem et al).

The addition of cetuximab in patients with KRAS wild type disease to chemotherapy resulted in significant improvements in overall survival with the median survival 23.5 versus 20 months, progression free survival median 9.9 versus 8.4 months and response rates of 57.3% versus 39.7% compared with FOLFIRI alone, confirming KRAS as a powerful biomarker predictor for cetuximab efficacy. (Van Cutsem E et al).

Benefits in patients treated with panitumumab limited to wild type KRAS tumors.

KRAS mutations are variable in their biologic characteristics and our tumor type specific.

KRAS in colorectal tumors have both codon 12 and codon 13 mutations 79% and 17.6%, respectively.

In cetuximab treated patients the presence of a glycine (G) to aspartic acid (D) change at codon 13 of KRAS and is associated with the intermediate survival, between that of patients with KRAS wild type tumors and tumors harboring a KRAS Smutation at glycine-12.

A retrospective review examining the effects of KRAS mutations on tumor response in unresectable colorectal liver metastases revealed worse overall outcomes and lower rates of conversion to resection with combination hepatic arterial infusion (HAI) pump therapy and systemic chemotherapy when compared against wild-type KRAS.

 

KRAS-wild­ type patients have a more pronounced response to HAI therapy compared with patients with KRAS mutations.

Smoking a strong associated with KRAS mutations in lung cancer.

KRAS mutations in more common in adenocarcinoma of the lung (20–40%) and less common, about 5%, in squamous non-small cell lung cancer.

KRAS is more common in cigarette smokers versus non-smokers (30% versus 11%) and in Western versus Asian populations (26% versus 11%).

The presence of a KRAS gene mutation in colorectal cancer is associated with worse prognosis for liver metastases as well as shorter survival following resection.

KRAS mutated pancreatic cancers which are 75-95% of the lesions, are almost invariably codon 12 mutations.

In small cell lung cancer more than 90% of KRAS mutations are located in codon 12.

Agents that show efficacy in treating KRAS G12 C mutated cancers include sotorasib, adagrasib and divarasib.

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