4WA7, 1D8D, 1D8E, 3GFT, 4DSN, 4DSO, 4EPR, 4EPT, 4EPV, 4EPW, 4EPX, 4EPY, 4L8G, 4LDJ, 4LPK, 4LRW, 4LUC, 4LV6, 4LYF, 4LYH, 4LYJ, 4M1O, 4M1S, 4M1T, 4M1W, 4M1Y, 4M21, 4M22, 4NMM, 4OBE, 4PZY, 4PZZ, 4Q01, 4Q02, 4Q03, 4QL3, 4TQ9, 4TQA, 4DST, 4DSU, 5F2E,%%s2MSC, 2MSD, 2MSE384516653ENSG00000133703ENSMUSG00000030265P01116P32883NM_004985NM_033360NM_001369786NM_001369787NM_021284NP_004976NP_203524NP_001356715NP_001356716NP_004976.2NP_001390173NP_001390174NP_001390175KRAS (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 transforming protein that results is implicated in various malignancies, including lung adenocarcinoma,[10] mucinous adenoma, ductal carcinoma of the pancreas and colorectal cancer.

[19][20] As of 2006, KRAS mutation was predictive of a very poor response to panitumumab (Vectibix) and cetuximab (Erbitux) therapy in colorectal cancer.

Studies show patients whose tumors express the mutated version of the KRAS gene will not respond to cetuximab or panitumumab.

[24] As of 2012, it was known that emergence of KRAS mutations was a frequent driver of acquired resistance to cetuximab anti-EGFR therapy in colorectal cancers.

It suggests to perform an early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.

[25] KRAS gene can also be amplified in colorectal cancer and tumors harboring this genetic lesion are not responsive to EGFR inhibitors.

[29][30][31] Lung cancer patients who are positive for KRAS mutation (and the EGFR status would be wild type) have a low response rate to erlotinib or gefitinib estimated at 5% or less.

[32] No correlation to survival was observed in 72% of all studies with KRAS sequencing performed in non-small cell lung cancer (NSCLC).

[32] A 2008 paper published in Cancer Research concluded that the in vivo administration of the compound oncrasin-1 "suppressed the growth of K-ras mutant human lung tumor xenografts by >70% and prolonged the survival of nude mice bearing these tumors, without causing detectable toxicity", and that the "results indicate that oncrasin-1 or its active analogues could be a novel class of anticancer agents which effectively kill K-Ras mutant cancer cells.

[34] Another KRAS inhibitor, MRTX1133 targets G12D mutation which is present in over 40% of PDACs[37][38] is currently in clinical trials to treat solid tumors including pancreatic adenocarcinoma.

If the test result indicates that the KRAS mutations are absent in the colorectal cancer cells, then the patient may be considered for treatment with Erbitux.

[48][49] A second is adagrasib (MRTX-849, Mirati Therapeutics)[50][51] while JNJ-74699157 (also known as ARS-3248, Wellspring Biosciences/Janssen) has received an investigational new drug (IND) approval to start clinical trials.

The novel strategy proposes finding small glue molecules, which attach the mutated KRAS to the GAP, prohibiting uncontrolled cell growth and restoring the normal function.

For this goal a theoretical KRAS-GAP conformation was designed with a several Å gap between the molecules, and a high-throughput in silico docking was performed for finding gluing agents.

[62] As of 2022 Revolution Medicines was exploring a small molecule therapy and reported anti-tumor activity in KRAS-G12D mutant tumor models.

[63] In 2021, the first clinical trial of a gene therapy targeting KRAS G12D was recruiting patients, sponsored by the National Cancer Institute.

[64] In June 2022, a case report was published about a 71-year-old woman with metastatic pancreatic cancer after extensive treatment (Whipple Surgery, radiation and multiple agent chemotherapy) who received a single infusion of her blood with engineered T cells with 2 genes encoding T cell receptors, directed to both the G12D mutation and an HLA allele (HLA-C*08:02).