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

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:26173780", "kind": "science-record", "revision": 6, "content_hash": "sha256:deb1e9f48d43b1cfe5eb9361c773927b57549c155f492a832d8875aca192274e", "created_at": "2026-11-01T15:40:09Z", "updated_at": "2026-11-01T21:20:01Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Mutant KRAS associated malic enzyme 1 expression is a predictive marker for radiation therapy response in non-small cell lung cancer.", "doi": "10.1186/s13014-015-0457-x", "pmid": "26173780", "authors": ["Gaurab Chakrabarti"], "journal": "Radiation oncology (London, England)", "year": 2015, "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.\nFINDINGS: 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.\nCONCLUSIONS: KRAS driven glutamine metabolism genes, specifically ME1 and GOT1 reactions, may be a predictive marker and potential therapeutic target for radiotherapy in NSCLC.", "claims": [{"id": "claim-method", "statement": "Kaplan-Meier survival plot and the hazard ratio with 95 % confidence intervals and logrank P value is calculated with the Bioconductor package in R.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:26173780", "locator": "sections[8] \"Kaplan-Meier statistics\" paragraph 2", "quote": "Kaplan-Meier survival plot and the hazard ratio with 95 % confidence intervals and logrank P value is calculated with the Bioconductor package in R."}], "state": "complete"}, {"id": "claim-data-access", "statement": "All human data is sourced through The Cancer Genome Atlas (http://cancergenome.nih.gov/), no patients were approached for this study. No consent and no ethical approval were required to utilize this database.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:26173780", "locator": "sections[9] \"Ethical approval and consent\" paragraph 2", "quote": "All human data is sourced through The Cancer Genome Atlas (http://cancergenome.nih.gov/), no patients were approached for this study. No consent and no ethical approval were required to utilize this database."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": null, "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:26173780"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE40606"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE40606"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:26173780", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1186/s13014-015-0457-x", "sha256": "sha256:5b467960999b4e347c502136386611843d8b1804e72dd9763f352d94654e63d3", "bytes": 25999, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1186/s13014-015-0457-x", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC4502640", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE40606", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE40606", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE40606", "version": null, "note": "All human data is sourced through The Cancer Genome Atlas (http://cancergenome.nih.gov/), no patients were approached for this study. No consent and no ethical approval were required to utilize this database.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "All human data is sourced through The Cancer Genome Atlas (http://cancergenome.nih.gov/), no patients were approached for this study. No consent and no ethical approval were required to utilize this database.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM997776", "GSM997777", "GSM997778", "GSM997779", "GSM997780", "GSM997781", "GSM997782", "GSM997783", "GSM997784", "GSM997785", "GSM997786", "GSM997787"], "sample_count": 12, "group_sizes": null, "group_sizes_basis": null, "platform": "6887", "taxon": "Mus musculus", "title": "Genome-wide analysis of tumor regression upon K-RAS inactivation", "resolution_checked_at": "2026-11-01T15:39:54Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "asset:table:pmid:26173780:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:3283998dde07e18bcc1ba9aec86d9520c3497821c1a487e31e60e648def23156", "bytes": 406, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[2]/table-wrap[1]#Tab1", "version": null, "note": "GSEA results for mutant vs. wild-type KRAS NSCLC cell lines", "structure": {"pmcid": "PMC4502640", "section_index": 2, "section_title": "Mutant KRAS is associated with ME1 and GOT1 expression in NSCLC", "row_count": 4, "column_count": 4}, "table": {"label": "Table 1", "caption": "GSEA results for mutant vs. wild-type KRAS NSCLC cell lines", "rows": [["Name", "NES", "Genes", "NOM p-val"], ["NITROGEN_METABOLISM", "1.59", "GLS", ".001"], ["GLUTAMATE_METABOLISM", "1.59", "GOT1, GOT2, GLS", ".001"], ["CARBON_FIXATION", "1.48", "ME1, ME3, GOT1, GOT2, MDH1", ".037"]], "row_count": 4, "column_count": 4, "numeric_cells": 6, "header_rows": 1, "locator": "section[2]/table-wrap[1]#Tab1"}}], "gaps": ["asset:data:geo:GSE40606 not downloaded", "asset:data:geo:GSE40606 licence not read"]}, "analysis": {"state": "complete", "methods": [{"id": "method-1", "family": "survival_analysis", "specific": "kaplan_meier", "label": "Survival analysis", "dsl_operations": ["survival_km"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "Kaplan-Meier survival plot and the hazard ratio with 95 % confidence intervals and logrank P value is calculated with the Bioconductor package in R."}}, {"id": "method-2", "family": "survival_analysis", "specific": "cox_proportional_hazards", "label": "Survival analysis", "dsl_operations": ["cox_ph"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.8, "band": "high", "quote": "Cox regression"}}, {"id": "method-3", "family": "survival_analysis", "specific": "log_rank_test", "label": "Survival analysis", "dsl_operations": ["logrank_test"], "missing_operations": [], "expressible": true, "parameters": {"hazard_ratio": "r survival plot and the hazard ratio with 95 % confidence in", "p_value": "e intervals and logrank P value is calculated with the"}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.8, "band": "high", "quote": "logrank"}}], "targets": [], "gaps": []}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["survival_km"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: kaplan_meier."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE40606"], "resolved_accessions": ["GSE40606"], "statements": ["All human data is sourced through The Cancer Genome Atlas (http://cancergenome.nih.gov/), no patients were approached for this study. No consent and no ethical approval were required to utilize this database."], "basis": "The paper names GSE40606 in Cancer Cell Line Encyclopedia (CCLE), GEO, The Cancer Genome Atlas (TCGA), and Project Achilles and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["survival_km"], "assets": ["source:pmid:26173780", "data:geo:GSE40606", "asset:table:pmid:26173780:1"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE40606"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": null, "independence": "same_provider"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 0, "usage": {}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:26173780", "type": "paper", "label": "pmid:26173780"}, {"id": "source:pmid:26173780", "type": "manuscript", "label": "PMID 26173780 full text"}, {"id": "data:geo:GSE40606", "type": "dataset", "label": "GEO GSE40606"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:26173780", "type": "paper", "label": "pmid:26173780"}, {"id": "source:pmid:26173780", "type": "manuscript", "label": "PMID 26173780 full text"}, {"id": "data:geo:GSE40606", "type": "dataset", "label": "GEO GSE40606"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-26173780", "type": "extraction", "used": ["source:pmid:26173780"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE40606", "type": "accession_resolution", "used": ["data:geo:GSE40606"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:26173780", "parent_hash": "sha256:15e3397030dec30142187736b13520afdd1dcd82cf8e453ac7978638e9416d21", "fork_of": null, "generation": 5}, "gaps": ["asset:data:geo:GSE40606 licence not read", "asset:data:geo:GSE40606 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["esistance. FINDINGS: A doxycycline-inducible mouse model of KRAS (G12D) driven NSCLC and patient data", "to be mutant KRAS associated in both a NSCLC mouse model and human NSCLC cancer cell lines. Perturbin", "esistance. FINDINGS: A doxycycline-inducible mouse model of KRAS (G12D) driven NSCLC and patien", "to be mutant KRAS associated in both a NSCLC mouse model and human NSCLC cancer cell lines. Per"], "order_basis": "paper_text_order:808", "id": "assay:1"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["survival_km"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Kaplan-Meier survival plot and the hazard ratio with 95 % confidence intervals and logrank P value is calculated with the Bioconductor package in R."], "order_basis": "consumes_earlier_output", "id": "assay:2"}]}