A 61-year-old man comes to the office due to 4 months of easy fatigability, anorexia, and a 4.5-kg (10-lb) unintentional weight loss. His stool occult blood testing is positive, and laboratory studies show microcytic hypochromic anemia. Colonoscopy reveals a 6-cm (2.4-in) mass in the descending colon. Biopsy samples obtained during the procedure are consistent with adenocarcinoma. A subsequent CT scan of the abdomen shows multiple metastatic liver lesions. Therapy with monoclonal antibodies that bind to epidermal growth factor receptors on the malignant cells is considered. An activating mutation in which of the following will most likely make this therapy ineffective?

Question

A 61-year-old man comes to the office due to 4 months of easy fatigability, anorexia, and a 4.5-kg (10-lb) unintentional weight loss.  His stool occult blood testing is positive, and laboratory studies show microcytic hypochromic anemia.  Colonoscopy reveals a 6-cm (2.4-in) mass in the descending colon.  Biopsy samples obtained during the procedure are consistent with adenocarcinoma.  A subsequent CT scan of the abdomen shows multiple metastatic liver lesions.  Therapy with monoclonal antibodies that bind to epidermal growth factor receptors on the malignant cells is considered.  An activating mutation in which of the following will most likely make this therapy ineffective?

Quizplus · Accepted Answer

11ec160b_39f3_24cb_9249_edf682911ad5_MD0001_00 Epidermal growth factor receptor (EGFR) is stimulated in a paracrine or autocrine fashion by its ligands, leading to the downstream activation of KRAS, a membrane-bound GTP-binding protein that stimulates cellular growth and proliferation. Many cancers (eg, colorectal, pancreas) leverage this system to drive unchecked cellular growth by overexpressing EGFR and its ligands or by developing constitutive activating mutations in the KRAS proto-oncogene. The EGFR signaling system can be targeted for cancer treatment through the use of monoclonal antibodies (eg, cetuximab, panitumumab) that block EGFR, leading to reduced KRAS stimulation and decreased cellular growth. However, this treatment is only effective for tumors with wild-type (normal) KRAS. Tumors with KRAS-activating mutations are resistant to anti-EGFR agents as they have a constitutive activation of a downstream signal that is independent of EGFR stimulation or blockade. Prior to the use of anti-EGFR agents, genetic testing of tumor tissue is performed to see if KRAS is wild-type (eligible for treatment) or mutated (noneligible). (Choice A) Adenomatous polyposis coli is a tumor suppressor protein that helps degrade beta-catenin, preventing uncontrolled cell growth. Inherited inactivating gene mutations are responsible for familial adenomatous polyposis. (Choice C) p53 is a tumor suppressor protein involved in DNA repair, apoptosis, and cell cycle control; mutations or deletions are present in a large percentage of human tumors. (Choice D) Platelet-derived growth factor stimulates formation of new blood vessels and proliferation of fibroblasts and smooth muscle cells by binding to a receptor tyrosine kinase; mutations resulting in overexpression encourage tumor growth by promoting uncontrolled angiogenesis. (Choice E) Vascular endothelial growth factor (VEGF) is the dominant growth factor involved in angiogenesis and lymph vessel development. Overexpression of VEGF promotes tumor vascularization, facilitating the growth and metastasis of cancers. Educational objective: Activating mutations of the KRAS gene lead to constitutive activation of the epidermal growth factor receptor (EGFR) pathway, promoting increased cell proliferation and growth. Tumors harboring these mutations are resistant to treatment with anti-EGFR drugs (eg, cetuximab, panitumumab). __________ References: KRAS mutation testing in metastatic colorectal cancer. (http://www.ncbi.nlm.nih.gov/pubmed/23066310) Clinical relevance of KRAS in human cancers. (http://www.ncbi.nlm.nih.gov/pubmed/20617134)

A 61-Year-Old Man Comes to the Office Due to 4