KRAS gene mutation and amplification status affects sensitivity to antifolate therapy
Testing patients with non-small cell lung cancer for both mutations and amplifications of the KRAS gene prior to therapy may help to predict response to treatment with antifolates, according to the updated results of a preclinical study presented at the AACR Annual Meeting 2012, held here March 31 - April 4.
Patients, especially those with lung cancer, who have KRAS gene mutations have a worse prognosis and do not respond well to targeted therapies, according to Sarah Bacus, Ph.D., Quintiles senior vice president and chief scientific officer of translational research and development, oncology. The results suggest that although these mutations are linked to a poor response to targeted therapies, they may predict response to treatment with antifolates, as long as the number of mutant genes is not amplified.
She and her colleagues assessed the relationship between antifolate medications and KRAS mutations and amplification, where the gene has an excess number of copies.
The preliminary results of the study were presented in November at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics. Researchers treated human non-small cell lung cancer cell lines (KRAS wild type, KRAS-mutant nonamplified and KRAS-mutant amplified) with the antifolates methotrexate or pemetrexed.
In lung cancer, the KRAS-mutant tumors need the folate pathway, which is associated with the growth of cancer. Treatment with the antifolate pemetrexed led to dramatic responses in patients with KRAS-mutant lung cancer. Patients with KRAS-wild type were less responsive. The researchers found a similar trend in KRAS-mutant lung cancer cell lines. When cell lines with KRAS mutations were deprived of access to this pathway, they failed to grow. However, this response was not seen if the number of copies of the KRAS-mutant gene was amplified or if the KRAS was wild type.
"KRAS mutations are most frequently observed in pancreatic, colorectal, lung, endometrial and biliary tract cancers, and as such, antifolates may have utility in the treatment of these cancers alone or in combination with other chemotherapies such as DNA-damaging agents," Bacus said.
She recommended that before prescribing an antifolate, whether in lung cancer or other cancers where KRAS mutations are prevalent, physicians should test for KRAS mutation and amplification, because the study results suggest that patients are likely to respond well only if the KRAS gene is mutated and not amplified.
More information: KRAS mutation and amplification status predicts sensitivity to antifolate therapies in Non Small Cell Lung Cancer
Somatic genetic mutation in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene has been linked to poor prognosis and resistance to various targeted therapeutics in Non Small Cell Lung Cancer (NSCLC). Therapeutic strategies that target tumors harboring these mutations represent an unmet medical need. In this study, we investigated the relationship between antifolate sensitivity and KRAS mutation/amplification status in NSCLC.
Human NSCLC cell lines (KRAS wild type, KRAS mutant non-amplified and KRAS mutant amplified) were treated with Methotrexate (MTX) or Pemetrexed (PEM) and assayed for proliferation. In these studies, KRASwt (wildtype) and KRASmut (mutant) amplified cells showed resistance to MTX treatment (IC50 >10μM). In contrast, growth of all KRASmut non-amplified cell lines studied was inhibited with MTX treatment (IC50 <100nM). Similar effects were observed for PEM in this study. Interrogation of the NCI Developmental Therapeutics Program drug screen database for the relationship between KRAS mutation status and drug efficacy also revealed a similar trend in other NSCLC cell lines for MTX and other anti-folates. qPCR analysis demonstrated a dramatic downregulation of KRAS gene expression in KRASwt and KRASmut cells with antifolate treatment. However, KRAS gene expression was less affected in antifolate treated KRASmut amplified cells. Co-treatment of KRASmut cells with antifolates and hypoxanthine/thymidine (which compensate for folate pathway inhibition) prevented downregulation of KRAS gene expression and rescued KRASmut cells. qPCR array analysis of miRNA expression in antifolate treated cells revealed increased expression of specific miRNAs, including miR-181c, with treatment compared to untreated controls. Transfection of a miR-181c mimic led to downregulation of KRAS gene expression in cells. Furthermore, antagomirs targeting miR-181c partially inhibited the downregulation of KRAS by antifolates. Importantly, we present clinical data describing rapid and durable radiographic responses in KRAS mutant NSCLC cancer patients.
Collectively, these studies identify higher sensitivity to antifolates in KRASmut non-amp NSCLC cell lines. Antifolate therapies decrease KRAS gene expression in KRASwt and KRASmut but do not do so in KRASmut amplified cells. We propose that decreased KRAS gene expression is detrimental to KRASmut cells due to their dependency on this survival pathway. We also propose that decreases in KRAS gene expression are mechanistically linked to stress (folate inhibition) induced miRNA expression which target KRAS gene expression. Overall, antifolates represent a novel method to target KRAS and as such should be investigated further for use in this subtype of NSCLC. As clinical evidence emerges, both KRAS mutation and amplification status should be incorporated for patient stratification prior to antifolate treatment.
Provided by American Association for Cancer Research
- Antifolates show promise against NSCLC subtype Nov 14, 2011 | not rated yet | 0
- Combination therapies for drug-resistant cancers Oct 10, 2011 | not rated yet | 0
- Gene linked to pancreatic cancer growth, study finds Jan 31, 2012 | not rated yet | 0
- Ganetespib showed activity in KRAS-mutant NSCLC as monotherapy and in combinations Jan 11, 2012 | not rated yet | 0
- Potential treatment target for KRAS-mutated colon cancer found Feb 16, 2012 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
In recent years, microRNAs (miRNAs) and other non-coding RNAs are small molecules that help control the expression of specific proteins. In recent years they have emerged as disease biomarkers. miRNA profiles have been used ...
Cancer 10 hours ago | not rated yet | 0
Cancer cells spread and grow by avoiding detection and destruction by the immune system. Stimulation of the immune system can help to eliminate cancer cells; however, there are many factors that cause the immune system to ...
Cancer 10 hours ago | not rated yet | 0
Researchers from London's Kingston University have begun a two-year study which could help prolong the lives of people with colorectal tumours.
Cancer 14 hours ago | 5 / 5 (1) | 0
Transformative research from Western University has identified new hormones in the body which may suppress breast cancer and stimulate the regression of breast tumors.
Cancer 14 hours ago | 5 / 5 (1) | 0
(Medical Xpress)—Curtin University researchers have found evidence that targeting specific cells in the body can reverse the effects of cancer on the immune system.
Cancer 15 hours ago | 5 / 5 (3) | 0
(Medical Xpress)—A new study by researchers in the US has shown that an ancient virus can be modified to help in the fight against the simian immunodeficiency virus SIV, which is the equivalent in monkeys ...
14 hours ago | 5 / 5 (3) | 0 |
Two mutations central to the development of infantile myofibromatosis (IM)—a disorder characterized by multiple tumors involving the skin, bone, and soft tissue—may provide new therapeutic targets, according to researchers ...
8 hours ago | 3 / 5 (2) | 0 |
Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.
11 hours ago | 5 / 5 (2) | 0 |
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to ...
11 hours ago | 5 / 5 (3) | 0 |
Talking on a hands-free device while behind the wheel can lead to a sharp increase in errors that could imperil other drivers on the road, according to new research from the University of Alberta.
8 hours ago | not rated yet | 0
(Medical Xpress)—Patients with diabetes who are depressed are much more likely to develop episodes of dangerously low blood sugars, or hypoglycemia, than are those who are not depressed, a new study has ...
15 hours ago | not rated yet | 0 |