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Mutant KRAS associated malic enzyme 1 expression is a predictive marker for radiation therapy response in non-small cell lung cancer.

Chakrabarti G - Radiat Oncol (2015)

Bottom Line: We hypothesized that mutant KRAS can regulate glutamine metabolism genes in NSCLC and maintain tumor redox balance through transamination reactions that generate cytosolic NADPH via malic enzyme 1 (ME1), which may contribute to radioresistance.A doxycycline-inducible mouse model of KRAS (G12D) driven NSCLC and patient data was analyzed from multiple publicly accessible databases including TCGA, CCLE, NCBI GEO and Project Achilles.ME1 expression was found to be mutant KRAS associated in both a NSCLC mouse model and human NSCLC cancer cell lines.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA. gaurab.chakrabarti@utsouthwestern.edu.

ABSTRACT

Background: Advanced non-small cell lung cancer (NSCLC) is an aggressive tumor that is treated with a combination of chemotherapy and radiation if the patient is not a candidate for surgery. Predictive biomarkers for response to radiotherapy are lacking in this patient population, making it a non-tailored therapy regimen with unknown outcome. Twenty to 30 % of NSCLC harbor an activating mutation in KRAS that may confer radioresistance. We hypothesized that mutant KRAS can regulate glutamine metabolism genes in NSCLC and maintain tumor redox balance through transamination reactions that generate cytosolic NADPH via malic enzyme 1 (ME1), which may contribute to radioresistance.

Findings: A doxycycline-inducible mouse model of KRAS (G12D) driven NSCLC and patient data was analyzed from multiple publicly accessible databases including TCGA, CCLE, NCBI GEO and Project Achilles. ME1 expression was found to be mutant KRAS associated in both a NSCLC mouse model and human NSCLC cancer cell lines. Perturbing glutamine metabolism sensitized mutant KRAS, but not wild-type KRAS NSCLC cell lines to radiation treatment. NSCLC survival analysis revealed that patients with elevated ME1 and GOT1 expression had significantly worse outcomes after radiotherapy, but this was not seen after chemotherapy alone.

Conclusions: KRAS driven glutamine metabolism genes, specifically ME1 and GOT1 reactions, may be a predictive marker and potential therapeutic target for radiotherapy in NSCLC.

No MeSH data available.


Related in: MedlinePlus

GOT1 and ME1 expression predicts response to radiation therapy in NSCLC patients. a Percent of complete responders to ionizing radiation (IR) in NSCLC patients separated based on KRAS status. Total number of complete responders in TCGA database = 14; wild-type KRAS = 13, mutant KRAS responders = 1. OR = odds ratio. Results compared using Fisher’s exact test. b, cME1 and GOT1 log2 mRNA expression levels with calculated mean from TCGA NSCLC patients prior to radiation treatment with associated patient outcome after radiation treatment, CR = complete response, disappearance of all target lesions; PD = progressive disease, >20 % increase in the sum of the longest diameter of target lesions. Multiple probes integrated for each gene. d, e Kaplan-Meier overall survival curves in IR-treated NSCLC patients from KMPLOT database separated into high and low GOT1 and ME1 expression. Total number of NSCLC patients analyzed = 73; number of patients with high expression: ME1 = 40, GOT1 = 45; number of patients with low expression: ME1 = 33, GOT1 = 28. All results were compared using Student’s t-tests or a Cox regression analysis unless otherwise stated. *p < 0.05; **p < 0.01; ***p < .001
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Fig3: GOT1 and ME1 expression predicts response to radiation therapy in NSCLC patients. a Percent of complete responders to ionizing radiation (IR) in NSCLC patients separated based on KRAS status. Total number of complete responders in TCGA database = 14; wild-type KRAS = 13, mutant KRAS responders = 1. OR = odds ratio. Results compared using Fisher’s exact test. b, cME1 and GOT1 log2 mRNA expression levels with calculated mean from TCGA NSCLC patients prior to radiation treatment with associated patient outcome after radiation treatment, CR = complete response, disappearance of all target lesions; PD = progressive disease, >20 % increase in the sum of the longest diameter of target lesions. Multiple probes integrated for each gene. d, e Kaplan-Meier overall survival curves in IR-treated NSCLC patients from KMPLOT database separated into high and low GOT1 and ME1 expression. Total number of NSCLC patients analyzed = 73; number of patients with high expression: ME1 = 40, GOT1 = 45; number of patients with low expression: ME1 = 33, GOT1 = 28. All results were compared using Student’s t-tests or a Cox regression analysis unless otherwise stated. *p < 0.05; **p < 0.01; ***p < .001

Mentions: To expand our in vivo and in vitro findings into a clinical context, we analyzed mutant KRAS status, tumor mRNA expression and RECIST outcomes data from the TCGA in lung adenocarcinoma (LUAD) NSCLC patients who were treated with IR (patient characteristics Additional file 2: Table S1 and Additional file 3: Table S2, https://tcga-data.nci.nih.gov/tcga/tcgaCancerDetails.jsp?diseaseType=LUAD&diseaseName=Lungadenocarcinoma) [25]. Of the 14 LUAD NSCLC patients who had a complete response (CR) to IR treatment, ~93 % (13/14) of the patient’s tumors were wild-type KRAS, while only ~7 % (1/14) of the tumors were mutant KRAS, suggesting that wild-type KRAS tumors may be more radiosensitive compared to mutant KRAS tumors, consistent with previous reports (Fig. 3a) [6–12]. ME1 and GOT1 expression levels were significantly elevated in those patients who had progressive disease (PD) when treated with IR vs patients who demonstrated a CR after radiation therapy (Fig. 3b, c). Furthermore, we assessed overall survival outcomes in IR treated NSCLC patients (n = 73) grouped into high or low GOT1 and ME1 expressers. Interestingly, we found that patients with high expression of GOT1 or ME1 had significantly worse prognosis over a 140 month time period when compared to low GOT1 or ME1 expressers (Fig. 3d, e). Lastly, we did not observe a significant median survival difference between high and low GOT1/ME1 expressers in NSCLC patients who received chemotherapy, but not IR (Additional file 4: Figure S2A, B). Taken together, this suggests that ME1 and GOT1 are predictors to radiation, but not chemotherapeutic, response in NSCLC.Fig. 3


Mutant KRAS associated malic enzyme 1 expression is a predictive marker for radiation therapy response in non-small cell lung cancer.

Chakrabarti G - Radiat Oncol (2015)

GOT1 and ME1 expression predicts response to radiation therapy in NSCLC patients. a Percent of complete responders to ionizing radiation (IR) in NSCLC patients separated based on KRAS status. Total number of complete responders in TCGA database = 14; wild-type KRAS = 13, mutant KRAS responders = 1. OR = odds ratio. Results compared using Fisher’s exact test. b, cME1 and GOT1 log2 mRNA expression levels with calculated mean from TCGA NSCLC patients prior to radiation treatment with associated patient outcome after radiation treatment, CR = complete response, disappearance of all target lesions; PD = progressive disease, >20 % increase in the sum of the longest diameter of target lesions. Multiple probes integrated for each gene. d, e Kaplan-Meier overall survival curves in IR-treated NSCLC patients from KMPLOT database separated into high and low GOT1 and ME1 expression. Total number of NSCLC patients analyzed = 73; number of patients with high expression: ME1 = 40, GOT1 = 45; number of patients with low expression: ME1 = 33, GOT1 = 28. All results were compared using Student’s t-tests or a Cox regression analysis unless otherwise stated. *p < 0.05; **p < 0.01; ***p < .001
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Fig3: GOT1 and ME1 expression predicts response to radiation therapy in NSCLC patients. a Percent of complete responders to ionizing radiation (IR) in NSCLC patients separated based on KRAS status. Total number of complete responders in TCGA database = 14; wild-type KRAS = 13, mutant KRAS responders = 1. OR = odds ratio. Results compared using Fisher’s exact test. b, cME1 and GOT1 log2 mRNA expression levels with calculated mean from TCGA NSCLC patients prior to radiation treatment with associated patient outcome after radiation treatment, CR = complete response, disappearance of all target lesions; PD = progressive disease, >20 % increase in the sum of the longest diameter of target lesions. Multiple probes integrated for each gene. d, e Kaplan-Meier overall survival curves in IR-treated NSCLC patients from KMPLOT database separated into high and low GOT1 and ME1 expression. Total number of NSCLC patients analyzed = 73; number of patients with high expression: ME1 = 40, GOT1 = 45; number of patients with low expression: ME1 = 33, GOT1 = 28. All results were compared using Student’s t-tests or a Cox regression analysis unless otherwise stated. *p < 0.05; **p < 0.01; ***p < .001
Mentions: To expand our in vivo and in vitro findings into a clinical context, we analyzed mutant KRAS status, tumor mRNA expression and RECIST outcomes data from the TCGA in lung adenocarcinoma (LUAD) NSCLC patients who were treated with IR (patient characteristics Additional file 2: Table S1 and Additional file 3: Table S2, https://tcga-data.nci.nih.gov/tcga/tcgaCancerDetails.jsp?diseaseType=LUAD&diseaseName=Lungadenocarcinoma) [25]. Of the 14 LUAD NSCLC patients who had a complete response (CR) to IR treatment, ~93 % (13/14) of the patient’s tumors were wild-type KRAS, while only ~7 % (1/14) of the tumors were mutant KRAS, suggesting that wild-type KRAS tumors may be more radiosensitive compared to mutant KRAS tumors, consistent with previous reports (Fig. 3a) [6–12]. ME1 and GOT1 expression levels were significantly elevated in those patients who had progressive disease (PD) when treated with IR vs patients who demonstrated a CR after radiation therapy (Fig. 3b, c). Furthermore, we assessed overall survival outcomes in IR treated NSCLC patients (n = 73) grouped into high or low GOT1 and ME1 expressers. Interestingly, we found that patients with high expression of GOT1 or ME1 had significantly worse prognosis over a 140 month time period when compared to low GOT1 or ME1 expressers (Fig. 3d, e). Lastly, we did not observe a significant median survival difference between high and low GOT1/ME1 expressers in NSCLC patients who received chemotherapy, but not IR (Additional file 4: Figure S2A, B). Taken together, this suggests that ME1 and GOT1 are predictors to radiation, but not chemotherapeutic, response in NSCLC.Fig. 3

Bottom Line: We hypothesized that mutant KRAS can regulate glutamine metabolism genes in NSCLC and maintain tumor redox balance through transamination reactions that generate cytosolic NADPH via malic enzyme 1 (ME1), which may contribute to radioresistance.A doxycycline-inducible mouse model of KRAS (G12D) driven NSCLC and patient data was analyzed from multiple publicly accessible databases including TCGA, CCLE, NCBI GEO and Project Achilles.ME1 expression was found to be mutant KRAS associated in both a NSCLC mouse model and human NSCLC cancer cell lines.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA. gaurab.chakrabarti@utsouthwestern.edu.

ABSTRACT

Background: Advanced non-small cell lung cancer (NSCLC) is an aggressive tumor that is treated with a combination of chemotherapy and radiation if the patient is not a candidate for surgery. Predictive biomarkers for response to radiotherapy are lacking in this patient population, making it a non-tailored therapy regimen with unknown outcome. Twenty to 30 % of NSCLC harbor an activating mutation in KRAS that may confer radioresistance. We hypothesized that mutant KRAS can regulate glutamine metabolism genes in NSCLC and maintain tumor redox balance through transamination reactions that generate cytosolic NADPH via malic enzyme 1 (ME1), which may contribute to radioresistance.

Findings: A doxycycline-inducible mouse model of KRAS (G12D) driven NSCLC and patient data was analyzed from multiple publicly accessible databases including TCGA, CCLE, NCBI GEO and Project Achilles. ME1 expression was found to be mutant KRAS associated in both a NSCLC mouse model and human NSCLC cancer cell lines. Perturbing glutamine metabolism sensitized mutant KRAS, but not wild-type KRAS NSCLC cell lines to radiation treatment. NSCLC survival analysis revealed that patients with elevated ME1 and GOT1 expression had significantly worse outcomes after radiotherapy, but this was not seen after chemotherapy alone.

Conclusions: KRAS driven glutamine metabolism genes, specifically ME1 and GOT1 reactions, may be a predictive marker and potential therapeutic target for radiotherapy in NSCLC.

No MeSH data available.


Related in: MedlinePlus