About

Graham C. Walker is a Professor of Biology at MIT and an American Cancer Society Professor. His research concentrates on understanding how proteins involved in DNA repair, mutagenesis, and cellular responses to DNA damage are regulated, with some discoveries having the potential to improve chemotherapy. Additionally, he studies the development of nitrogen-fixing nodules on legumes and the relationship between rhizobial functions required for nodule invasion and mammalian pathogenesis. Walker has received numerous awards and honors, including membership in the National Academy of Sciences, the Howard Hughes Medical Institute HHMI Professor title, and the Environmental Mutagen Society Award. His work has contributed significantly to the fields of DNA repair mechanisms and symbiotic nitrogen fixation.

Research topics

• Chemistry
• Biology
• Biochemistry
• Microbiology
• Genetics
• Physics
• Computational biology

Selected publications

• Biomarker prevalence in US patients with gastric/gastroesophageal junction adenocarcinoma (GEA) from real-world data.

  Journal of Clinical Oncology · 2026-01-10

  article

  444 Background: The therapeutic landscape for gastric (GA)/ gastroesophageal junction (GEJ) adenocarcinoma (GEA) has advanced with biomarker (BM)-targeted therapies. c-Met protein (also known as MET protein) is a potential target for antibody-drug conjugates; however, the prevalence and overlap of MET protein with key BMs in GEA are not well understood. Detailed molecular profiling from patients in real-world (RW) settings can inform patient selection and treatment strategies. Methods: We conducted a retrospective analysis of 1819 patient samples (1081 GEJ and 738 GA), with either treatment-naïve (70%) or treatment-experienced (30%) samples, using the Caris and linked ConcertAI Translational360 database to assess BM prevalence. Leveraging high concordance between c-Met immunohistochemistry (IHC) and RNA, we defined MET mRNA enriched tissue samples as the top quartile (Q1) of samples with the highest expression. Using IHC or transcriptomics, we assessed Jaccard overlap of MET Q1 with human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1) with combined positive scores of ≥1 or ≥5 (CPS1+ or CPS5+), claudin 18 (CLDN18), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) , and fibroblast growth factor receptor 2 (FGFR2) . Due to high concordance between CLDN18 IHC and RNA, we used Youden index analyses to predict enriched samples. Results: Consistent with previous literature, HER2 positivity (+), PD-L1 CPS1+, PD-L1 CPS5+ and CLDN18+ were detected in 149 (11%), 790 (76%), 347 (33%), and 752 (41.3%) of BM-evaluable samples, respectively, by IHC. There was no substantial over- or under-representation of MET Q1 across clinical variables. Overall, MET Q1 had relatively low concurrent expressions with HER2 and CLDN18. Among GEJ samples, MET Q1 overlapped with CLDN18+ (15%), HER2+ (8%), PD-L1 CPS1+ (29%), and PD-L1 CPS5+ (25%); in GA, MET Q1 overlapped with CLDN18+ (15%), HER2+ (4%), PD-L1 CPS1+ (19%), and PD-L1 CPS5+ (18%). Treatment in general reduced overlap between MET Q1 and PD-L1 (from 27% to 20%), which may be due to chemotherapy (27% to 18%), but not anti-PD1 therapy (27% to 36%). In HER2-negative populations, MET Q1 had a consistently low (11%–12%) overlap with FGFR2, whereas MET - CEACAM5 overlaps were numerically higher (21% in GEJ and 16% in GA). Additional GEA subtype analyses are ongoing. Conclusions: MET Q1 exhibits relatively low overlap with HER2, CLDN18, and FGFR2 , indicating different disease biology in these GEA subtypes. MET/ PD-L1 overlap decreased in treatment-experienced patients, thus favoring using anti-PD1 in earlier line of treatment. RW analysis of biomarker prevalence and overlap may support c-MET targeted clinical strategies.

  PublisherDOI

• Clinical significance of c-Met expression in patients with advanced gastroesophageal adenocarcinoma.

  Journal of Clinical Oncology · 2026-01-10

  article

  426 Background: The prognosis for advanced gastroesophageal adenocarcinoma (GEA) remains poor, highlighting the urgent need for novel therapeutic options. MET-targeted agents including antibody-drug conjugates are under clinical investigation in GEA. However, the prevalence and prognostic impact of c-Met expression across different treatment regimens remain unclear. Understanding c-Met expression and its correlation with treatment regimens and other biomarkers is crucial for refining patient selection and guiding therapeutic strategy. Methods: We retrospectively analyzed 400 patients (pts) with advanced GEA receiving first-line therapy at our institution. Immunohistochemistry was performed for c-Met, HER2, PD-L1, CLDN18, and FGFR2. Pts were classified as c-Met high vs. low using a threshold of ≥50% with ≥2+ staining. We assessed correlations between c-Met high and other biomarkers, as well as survival outcomes by treatment regimen: chemotherapy alone (CTx, n = 173), combination with immune checkpoint inhibitors (ICI, n = 130), and combination with molecular targeted agents (MTA, n = 97). Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier method, log-rank test and Cox proportional hazards models. Exploratory genomic characterization by next-generation sequencing was performed in 177 pts; transcriptomic analysis in 88 pts. Results: High c-Met expression was detected in 11.3% of pts by membrane staining th Ultraview detection kit, showing significant association with PD-L1 positivity (CPS≥5) (P < 0.05) but not other protein biomarkers. c-Met high pts exhibited a trend of shorter PFS in the overall cohort (HR = 1.34; 95% CI: 0.96-1.88; P = 0.086), most pronounced in MTA group (HR = 1.73; 95% CI: 0.95-3.14; P = 0.069). Multivariate analysis confirmed c-Met high as an independent worse prognostic factor for PFS (HR = 1.52; 95% CI: 1.05-2.20; P = 0.025). OS did not differ significantly in the overall cohort (HR = 1.11; 95% CI: 0.77-1.62; P = 0.575) but was notably worse in CTx group for c-Met high pts (HR = 1.89; 95% CI: 1.02-3.52; P = 0.040). Multivariate analysis in CTx cohort supported c-Met as an independent predictor of poor OS (HR = 3.30; 95% CI: 1.48-7.3; P = 0.003). Genomic analysis identified MET amplification in 2.3% (4/177). Transcriptomic analysis revealed significant correlations between c-Met high and elevated MET RNA expression (c-Met high vs. low, median TPM: 800 vs. 113, P = 0.003). Conclusions: c-Met high expression was significantly associated with worse PFS in general, and poor OS in pts treated with chemotherapy alone. Further investigation is warranted to elucidate mechanisms underlying poor outcomes in c-Met high GEA pts as well as expression correlation with recently approved c-Met CDx assay, which may help inform ongoing MET-targeted treatment strategies.

  PublisherDOI

• Exploiting Peptide Chirality and Transport to Dissect the Complex Mechanism of Action of Host Peptides on Bacteria

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-25

  preprintOpen accessSenior author

  Abstract Elucidation of the complex mechanisms of action of antimicrobial peptides (AMPs) is critical for improving their efficacy. A major challenge in AMP research is distinguishing AMP effects resulting from various protein interactions from those caused by membrane disruption. Moreover, since AMPs often act in multiple cellular compartments, it is challenging to pinpoint where their distinct activities occur. Nodule-specific cysteine-rich (NCR) peptides secreted by legumes, including NCR247, have evolved from AMPs to regulate differentiation of their nitrogen-fixing bacterial partner during symbiosis as well as to exert antimicrobial actions. At sub-lethal concentrations, NCR247 exhibits strikingly pleiotropic effects on Sinorhizobium meliloti . We used the L- and D-enantiomeric forms of NCR247 to distinguish between phenotypes resulting from stereospecific, protein-targeted interactions and those caused by achiral interactions such as membrane disruption. In addition, we utilized an S. meliloti strain lacking BacA, the transporter that imports NCR peptides into the cytoplasm. BacA plays critical symbiotic roles by reducing periplasmic peptide accumulation and fine-tuning symbiotic signaling. Use of the BacA-deficient strain made it possible to distinguish between phenotypes resulting from peptide interactions in the periplasm and those occurring in the cytoplasm. At high concentrations, both L- and D-NCR247 permeabilize bacterial membranes, consistent with nonspecific cationic AMP activity. In the cytoplasm, both NCR247 enantiomers sequester heme and trigger iron starvation in an achiral but BacA-dependent manner. However, only L-NCR247 activates bacterial two-component systems via stereospecific periplasmic interactions. By combining stereochemistry and genetics, this work disentangles the spatial and molecular complexity of NCR247 action. This approach provides critical mechanistic insights into how host peptides with pleiotropic functions modulate bacterial physiology. Author Summary Many organisms produce antimicrobial peptides (AMPs) to fight infections, but legumes have uniquely co-opted these molecules to control their symbiotic partners. During symbiosis between Medicago truncatula and Sinorhizobium meliloti , the plant secreted Nodule-specific Cysteine-Rich (NCR) peptides, transforms free-living bacteria into differentiated bacteroids that fix nitrogen but cannot reproduce outside the host. One such peptide, NCR247, exerts pleiotropic effects on the bacteria, acting on different subcellular locations, including membrane, heme, and proteins. Using a mirror-image (D-form) peptide, we disentangled peptide effects arising from generic physiochemical interactions versus stereospecific binding. The inner membrane protein BacA is known to play a protective role by importing NCR peptides into the cytoplasm. Using a bacterium lacking BacA, we were able to distinguish the effects of the peptide within and outside the cytoplasm. It was thought that BacA safeguards symbiotic bacteria by internalizing NCR peptides, thereby limiting their toxic membrane lytic effects, yet this has not been demonstrated. We show that BacA prevents lethal overstimulation of signaling pathways in the periplasm by internalizing the peptides. Our methods provide a framework for testing mechanism of action of new peptide-based antibiotics to combat multidrug-resistant bacteria.

  PublisherOA PDFDOI

• Telisotuzumab adizutecan (ABBV-400; Temab-A) in combination with fluorouracil, leucovorin, and budigalimab in locally advanced/metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma (a/m GEA).

  Journal of Clinical Oncology · 2025-05-28

  article

  TPS4202 Background: The MET proto-oncogene and its receptor tyrosine kinase gene product (c-Met protein) are involved in normal cellular functions such as cell proliferation and differentiation but can be abnormally activated and upregulated in cancer to promote tumor growth. MET gene amplification and increased c-Met protein expression are associated with poor survival outcomes in gastric cancer. The antibody-drug conjugate Temab-A (ABBV-400) is composed of the c-Met–directed antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor. A phase 1 study (NCT05029882) investigating Temab-A monotherapy demonstrated manageable safety and encouraging efficacy in patients with previously treated, advanced GEA, with an objective response rate of 29% (12/42) and clinical benefit rate of 71% (30/42) (Strickler et al. Ann Oncol . 2024;35:1439P). This study evaluates Temab-A in combination with fluorouracil (5-FU), leucovorin/folinic acid (LV), and budigalimab (budi; a PD-1–blocking antibody). Methods: This multicenter,phase 2, open-label, randomized study (NCT06628310) will enroll ~180 adult patients with HER2-negative a/m GEA who have not received prior systemic therapy in the a/m setting, have not received a prior PD-(L)1 inhibitor, have Eastern Cooperative Oncology Group performance status 0–1, and have measurable disease per RECIST v1.1. Primary objectives of the study are to evaluate safety and tolerability, evaluate efficacy as measured by progression-free survival and objective response, and select the recommended phase 3 dose of Temab-A in combination with 5-FU, LV, and budi. Secondary objectives include assessment of dose-limiting toxicities (DLTs) in the dose-escalation stage, evaluation of pharmacokinetics, and further evaluation of efficacy measures (duration of response, disease control, and overall survival). The study consists of 2 stages: dose escalation and dose optimization. During BOIN-directed dose escalation, ~18 patients receive escalating doses of Temab-A administered once every 4 weeks (Q4W) in combination with fixed doses of 5-FU (2400 mg/m 2 Q2W), LV (400 mg/m 2 Q2W), and budi (500 mg Q4W). DLTs are assessed during the first 28-day cycle. During dose optimization, ~162 patients are randomized 1:1:1 to 1 of 2 selected doses of Temab-A in combination with 5-FU, LV, and budi or a control arm of FOLFOX + budi. Randomization is stratified by PD-L1 expression and primary tumor location. Treatment is administered until disease progression, intolerable toxicity, or other discontinuation criteria are met. Either archived formalin-fixed paraffin-embedded tissue or a fresh biopsy is required for biomarker research that will include evaluation of c-Met protein expression and MET genomic alterations. Clinical trial information: NCT06628310 .

  PublisherDOI

• Sensitization of cancer cells to DNA-damaging agents by expression of the REV1 C-terminal domain: Implications for chemotherapy

  Proceedings of the National Academy of Sciences · 2025-09-10 · 1 citations

  articleOpen accessSenior authorCorresponding

  The mutagenic translesion synthesis (TLS) pathway, which is critically dependent on REV1's ability to recruit inserter TLS polymerases and the POLζ extender polymerase, enables cancer cells to bypass DNA lesions while introducing mutations that likely contribute to the development of chemotherapy resistance and secondary malignancies. Targeting this pathway represents a promising therapeutic strategy. Here, we demonstrate that the expression of the C-terminal domain (CTD) of human REV1, a ca. 100 amino acid scaffold essential for TLS polymerase interactions, disrupts REV1/POLζ-dependent TLS in mammalian cells. Inducible expression of REV1-CTD in multiple human and murine cancer cell lines sensitizes cells to DNA-damaging agents such as cisplatin, benzo[a]pyrene diol epoxide, and methyl methanesulfonate, without intrinsic cytotoxicity. REV1-CTD expression increases genomic instability, decreases mutagenesis, and enhances G2 arrest following genotoxic stress. Mutational disruption of the CTD's interaction interfaces abrogates these effects, confirming a dominant-negative mechanism via sequestration of TLS components. In a xenograft mouse model, REV1-CTD expression markedly enhances cisplatin efficacy, significantly reducing tumor burden. These findings establish the REV1-CTD as an effective dominant-negative inhibitor of TLS and support its development as a therapeutic agent delivered to cancer cells to enhance the efficacy of genotoxic chemotherapy.

  PublisherDOI

• Correction for Staehelin et al., “Exo-Oligosaccharides of <i>Rhizobium</i> sp. Strain NGR234 Are Required for Symbiosis with Various Legumes”

  Journal of Bacteriology · 2025-08-20

  erratumOpen access

  Volume 188, no. 17, p. 6168-6178, 2006, https://doi.org/10.1128/jb.00365-06. Page 6169: Fig. 1A should appear as shown in this correction. We have noticed that the chemical structure of the repeating subunit of the acidic EPS from strain NGR234 was incorrectly copied from the original paper (Djordjevic et al., 1986, Carbohydr Res 148:87-99). In the EPS of NGR234, both glucuronic acid residues adopt the α-anomeric configuration, as confirmed by Rodríguez-Navarro et al. 2014 [PLoS One 9(12): e115391]. This correction does not affect any conclusions drawn in our article. We apologize for any confusion or inconvenience this error may have caused.

  PublisherDOI

• Exploiting peptide chirality and transport to dissect the complex mechanism of action of host peptides on bacteria

  PLoS Genetics · 2025-12-11 · 1 citations

  articleOpen accessSenior authorCorresponding

  Elucidation of the complex mechanisms of action of antimicrobial peptides (AMPs) is critical for improving their efficacy. A major challenge in AMP research is distinguishing AMP effects resulting from various protein interactions from those caused by membrane disruption. Moreover, since AMPs often act in multiple cellular compartments, it is challenging to pinpoint where their distinct activities occur. Nodule-specific cysteine-rich (NCR) peptides secreted by some legumes, including NCR247, have evolved from AMPs to regulate differentiation of their nitrogen-fixing bacterial partner during symbiosis as well as to exert antimicrobial actions. At sub-lethal concentrations, NCR247 exhibits strikingly pleiotropic effects on Sinorhizobium meliloti. We used the L- and D-enantiomeric forms of NCR247 to distinguish between phenotypes resulting from stereospecific, protein-targeted interactions and those caused by non-specific interactions such as membrane disruption. In addition, we utilized an S. meliloti strain lacking BacA, a transporter that imports NCR peptides into the cytoplasm. The bacterial protein BacA, plays critical symbiotic roles by possibly reducing periplasmic peptide accumulation and fine-tuning symbiotic signaling. Use of the BacA-deficient strain made it possible to distinguish between phenotypes resulting from peptide interactions in the periplasm and those occurring in the cytoplasm. At high concentrations, both L- and D-NCR247 permeabilize bacterial membranes, consistent with nonspecific cationic AMP activity. In the cytoplasm, both NCR247 enantiomers sequester heme and trigger iron starvation in a chirality-independent but BacA-dependent manner. However, only L-NCR247 activates bacterial two-component systems via stereospecific periplasmic interactions. By combining stereochemistry and genetics, this work disentangles the spatial and molecular complexity of NCR247 action. This approach provides critical mechanistic insights into how host peptides with pleiotropic functions modulate bacterial physiology.

  PublisherDOI

• 3201 Evaluation of a new frailty on-call shift for geriatric SpRs at St Thomas' Hospital (STH)

  Age and Ageing · 2025-07-01

  articleSenior author

  Abstract Introduction Frailty-attuned acute hospital care is a vital component of integrated services for older people. The NHS Long Term Plan requires hospitals with major emergency departments to deliver 70 hours of acute frailty services each week. Workforce limitations often prevent services from meeting this target and expanding. Geriatric specialist registrars (SpRs) must gain experience in acute frailty so that the consultant workforce of the future can meet patient needs effectively. St Thomas’ Hospital (STH) Acute Frailty Service expanded hours of operation through the introduction of a frailty twilight SpR. The aim was to increase patients seen by the frailty service, enhance access to Comprehensive Geriatric Assessment (CGA) and provide learning opportunities in acute frailty. Method The twilight frailty SpR was introduced in October 2024 by re-allocating existing on-call resources, without using additional staffing. Retrospective data from April to November 2024 were analysed to compare patient numbers and service performance before and after implementation. Feedback was collected from SpRs on the learning opportunities and challenges encountered. Results Following introduction of the twilight frailty SpR, the average number of patients seen by the acute frailty team increased by 28.3%, from an average of 129 per month (April–September) to 166 per month (October–November). A survey of SpRs revealed that the majority felt twilight frailty shifts provided valuable learning experiences. Key benefits included increased autonomy and enhanced experience in CGA in an acute setting. Challenges included difficulties in discharging patients on the same day due to limited therapy support and the need for additional social care. Conclusion The introduction of a twilight frailty SpR extended acute frailty service hours and increased the number of patients receiving a CGA at the front door. SpRs have gained valuable experience in acute frailty management which is key in developing the consultant workforce of the future.

  PublisherDOI

• Larval settlement: Historical and future perspectives

  2025-12-23

  book-chapter1st authorCorresponding

  The barnacle cypris larva is initially a pelagic organism. During its planktonic phase the cyprid positions itself in the water column to maximise survival, dispersal and the chance of contacting the adult habitat; it responds to environmental cues - principally light and pressure - by active upward swimming and passive sinking. When the competent cyprid contacts a surface it moves on to the settlement phase. Contact with a surface is maintained by a temporary adhesive on the antennules allowing exploration of the surface when various factors are being sensed at different temporal and spatial scales. Two factors only, chemical cues and microbial films, have been selected for detailed discussion. The consummatory act of settlement is permanent fixation, when the cyprid cements itself down onto a surface. When the fixed cyprid has metamorphosed to the juvenile it is then considered to be recruited to the surface.

  PublisherDOI

• The BacA(SbmA) Importer of Symbiotically Important Legume Nodule Cysteine-Rich Peptides: Insights into Protein Architecture, Function, and Evolutionary Implications

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-20

  preprintOpen accessSenior authorCorresponding

  Abstract Some legumes encode families of NCR (Nodule-Cysteine-Rich) peptides that cause their rhizobial partners to terminally differentiate during the development of a nitrogen-fixing symbiosis. Sinorhizobium meliloti , whose plant hosts Medicago truncatula and M. sativa express ca . 600 NCR peptides during root nodule development, possesses a symbiotically essential BacA Sm protein that imports certain NCR peptides into the cytoplasm. This import permits proteolytic degradation of the NCR peptides, thereby protecting the endocytosed bacteria from their antimicrobial peptide-like lethality, while also allowing certain NCR peptides to undergo their symbiotically critical interactions with cytoplasmic components, for example heme-sequestration in the case of NCR247. BacA’s Escherichia coli ortholog SbmA Ec can restore a wildtype phenotype to a ΔbacA Sm mutant. Our study employed 54 S. meliloti bacA Sm missense mutants (35 to cysteine and 19 to glycine) that we tested for protein production, ability to establish a nitrogen-fixing symbiosis, and their susceptibility to killing by higher levels of the NCR247 and the Bac7(1-35) peptides. We also used the Single Cysteine Accessibility Method to make topological inferences. Our detailed genetic, biochemical, structural, and physiological analyses have revealed that BacA Sm and SbmA homodimers function as finely tuned import machines, whose structures can be relatively easily disrupted by single amino acid changes. Our discovery that several mutations that differentially separate nitrogen-fixation, NCR247 import, and Bac7(1-35) import map to the lining of the peptide-binding cavity in the outward-open SbmA/BacA conformation suggests a molecular explanation the other otherwise paradoxical observation that SbmA/BacAs from pathogens can fully replace BacA Sm , whereas BacAs from other rhizobia cannot. Significance Statement Sinorhizobium meliloti BacA Sm and Escherichia coli SbmA Ec are closely related proteins that function as homodimeric transporters to import peptides and other cargos through the cytoplasmic membrane into the cytoplasm. BacA is critical for S. meliloti to establish a nitrogen-fixing symbiosis with its legume hosts because of its ability to import Nodule Cysteine-Rich (NCR) nodule-specific plant peptides. This import protects the bacteria inside the nodule from the potentially lethal effects of these NCR peptides while also enabling NCRs to make their intracellular interactions that are necessary for symbiosis. Our extensive multidisciplinary studies offer new insights into function of BacA/SbmA transporters and provide a molecular explanation for why BacA/SbmA orthologs from mammalian pathogens can replace BacA Sm but those from other rhizobia cannot.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01CA021615

  NIH · $9.3M · 2022

• NIH Grant R01GM028988

  NIH · $1.7M · 1997

• NIH Grant R01ES015818

  NIH · $3.8M · 2018

• NIH Grant P01ES003926

  NIH · $8.6M · 1999

• NIH Grant R01GM031030

  NIH · $12.4M · 2023

Frequent coauthors

• Wolfram Siede

  University of North Texas

  63 shared

• C. Herman

  Massachusetts Institute of Technology

  36 shared

• Richard D’Ari

  36 shared

• David Thévenet

  Centre National de la Recherche Scientifique

  36 shared

• James J. Collins

  Massachusetts Institute of Technology

  36 shared

• Philippe Bouloc

  Centre National de la Recherche Scientifique

  36 shared

• Errol C. Friedberg

  The University of Texas Southwestern Medical Center

  34 shared

• Richard D. Wood

  The University of Texas MD Anderson Cancer Center

  32 shared

Awards & honors

• Revolutionizing Innovative, Visionary Environmental health R…
• R35 Outstanding Investigator Award (2017)
• National Academy of Sciences, Member (2013)
• Howard Hughes Medical Institute, HHMI Professor (2010)
• University of Guelph, Doctor of Science, honoris causa (2010…