Science brief: a reading aid, unvalidated by any person. Not a prediction and not advice. Public data only.

Science brief: KRAS inhibitor

As of 2025-12-31. Topic mode. Literature: KRAS inhibitor. 42 abstracts read, 24 claims checked, 0 papers had no abstract and were not read.

Read this first.

• Each claim was extracted by a model from one abstract. A second, separate reader then checked it against the abstracts in this pack, and a third checked that reader. Every line below carries two exact quotes that code found in the sources.
• The corpus is each lab's three most recent last-author papers at four year-ends, abstracts only. "No independent support found" means none in this corpus. It never means not replicated.
• The order is a published sort rule (scirank-v1): highest evidence tier among verified claims, then independent supports, then fewer contradictions. It is not a score and it predicts nothing.
• Evidence tier comes from the extraction's model-system field. "Randomized" is a word rule on the abstract.

Measured, once, on planted errors (an upper bound on real ones):

• One pass over the retrieved abstracts found 110 of 121 hard planted misstatements and named the paper that shows each (91%, 95% interval 85 to 96). It flagged 2 of 423 unaltered claims (false alarms).
• By type: a flipped direction 58 of 66 (88%, 81 to 94); a number swapped for another in the same abstract 35 of 37 (95%, 83 to 100); animal and human swapped 17 of 18 (too few for a rate).
• Baselines on the same claims: a read with no literature flagged 52% and could name no paper; the Lens with a string rule found 2%; fan-out over chunks found 89%, not better than one pass.
• Planted errors are an upper bound on real ones: one word or number was changed and the true paper was in the pack. No person has checked a real case. Reader and extractor are both Claude models; scoring was by code against a key.
• Supported records, the framed read and the ranking are not measured by this test.

Supported records, graded in session by two blind agents (20 drawn from real briefs, both graders must agree): 20 of 20 held (83% to 100%). The same graders rejected 20 of 20 controls that code built to disagree with their own paper. Model-graded, not human-verified: docs/methodology/scibrief-grading.md.

Extraction: Measured accuracy on a fresh sample (agent readers, both must agree): output_type right 97% (92%–99%); model_system right 95% (90%–98%); scale right 97% (93%–99%); claim supported 98% (94%–99%); effect numbers supported 99% (92%–100%); limitations supported 93% (85%–97%).

Where a paper disagrees with a claim

None found in this pack.

Labs by strength of evidence

Claims and their evidence

Ignacio Garrido‐Laguna, University of Utah

• C10 Oral LY3962673, a selective KRAS G12D inhibitor, is being evaluated alone and in combination in KRAS G12D-mutant solid tumors in a phase 1 trial.
  • human, randomized (by rule); verified against its paper; no independent support found in this corpus; source: MOONRAY-01, a phase 1 study of LY3962673, a potent, orally bioavailable, and selective KRAS G12D inhibitor in KRAS G12D -mutant solid tumors. (2025-01-27, P18)
  • Own paper:
    • claim: "Oral LY3962673, a selective KRAS G12D inhibitor, is being evaluated alone and in combination in KRAS G12D-mutant solid tumors in a phase 1 trial." / paper: "first-in-human phase 1 study of oral LY3962673 in participants (pts) with KRAS G12D -mutant solid tumors" — MOONRAY-01, a phase 1 study of LY3962673, a potent, orally bioavailable, and selective KRAS G12D inhibitor in KRAS G12D -mutant solid tumors. (2025-01-27, P18). The trial design describes the same phase 1 study of oral LY3962673 as monotherapy and in combinations. [R3996]

Peh Yean Cheah, Duke University

• C15 Anti-KRAS antibody can enter live colorectal mucosa-tumor cells, aggregate KRAS in the cytoplasm, hinder its translocation to the inner plasma membrane, and reduce SOX9 staining. Reported effect: Anti-KRAS antibody treated tumor cells have less intense SOX9 cytoplasmic and nuclear staining compared to untreated cells; no numeric effect size stated.
  • human; verified against its paper; no independent support found in this corpus; source: KRAS-specific antibody binds to KRAS protein inside colorectal adenocarcinoma cells and inhibits its localization to the plasma membrane (2023-03-27, P06)
  • Own paper:
    • claim: "can enter live colorectal mucosa-tumor cells, aggregate KRAS in the cytoplasm, hinder its translocation to the inner plasma membrane" / paper: "anti-KRAS antibody can enter live mucosa-tumor cells and specifically aggregate KRAS in the cytoplasm, thus hindering its translocation to the inner plasma membrane." — KRAS-specific antibody binds to KRAS protein inside colorectal adenocarcinoma cells and inhibits its localization to the plasma membrane (2023-03-27, P06). The paper reports the same internalization, aggregation, mislocalization and reduced SOX9 staining. [R4001]

Alessandro Davide Santin, Yale University

• C12 Avutometinib plus Defactinib produced a confirmed, long-lasting (4 years) partial response in a KRAS-mutated, platinum-resistant recurrent LGSOC patient progressing on Binimetinib. Reported effect: Confirmed partial response lasting 4 years; CA-125 returned to baseline; no dose-limiting toxicity or dose reduction over 4 years.
  • human; verified against its paper; no independent support found in this corpus; source: Long lasting response to the combination of Avutometinib and Defactinib after progression on Binimetinib in a patient with recurrent low grade serous ovarian carcinoma − A case report (2025-12-17, P09)
  • Own paper:
    • claim: "a confirmed, long-lasting (4 years) partial response" / paper: "she experienced a confirmed and long-lasting (4 years) partial response as well as a return of CA-125 to baseline." — Long lasting response to the combination of Avutometinib and Defactinib after progression on Binimetinib in a patient with recurrent low grade serous ovarian carcinoma − A case report (2025-12-17, P09). The case report states the same 4-year confirmed partial response in a KRAS-mutated LGSOC patient after Binimetinib. [R3998]

Lynn E. Heasley, University of Colorado Anschutz

• C18 Three novel murine KRAS G12C-driven lung cancer cell lines provide models for preclinical testing of KRAS G12C inhibitors and combination strategies in immune-competent hosts. Reported effect: Lines showed similar in vitro sensitivity but distinct in vivo MRTX-849 responses; MRTX-849/RMC-4550 caused tumor shrinkage in syngeneic mice, lost in nu/nu mice.
  • animal; verified against its paper; no independent support found in this corpus; source: Evaluation of KRASG12C inhibitor responses in novel murine KRASG12C lung cancer cell line models (2023-02-08, P26)
  • Own paper:
    • claim: "Three novel murine KRAS G12C-driven lung cancer cell lines provide models for preclinical testing of KRAS G12C inhibitors" / paper: "we generated three novel murine KRAS G12C -driven lung cancer cell lines." — Evaluation of KRASG12C inhibitor responses in novel murine KRASG12C lung cancer cell line models (2023-02-08, P26). The paper generates the same three murine lines and describes them as models for testing combinations in immune-competent hosts. [R4004]

Stephen W. Fesik, Vanderbilt University

• C09 BI-2493, a spirocyclized reversible pan-KRAS inhibitor, shows in vivo efficacy in various KRAS mutant and KRAS wild-type amplified xenograft models.
  • animal; verified against its paper; no independent support found in this corpus; source: Discovery of BI-2493, a Pan-KRAS Inhibitor Showing In Vivo Efficacy (2025-07-25, P07)
  • Own paper:
    • claim: "BI-2493, a spirocyclized reversible pan-KRAS inhibitor, shows in vivo efficacy in various KRAS mutant and KRAS wild-type amplified xenograft models" / paper: "BI-2493 shows in vivo efficacy in various KRAS mutant and KRAS wild-type amplified xenograft models and represents a promising starting point for further optimization." — Discovery of BI-2493, a Pan-KRAS Inhibitor Showing In Vivo Efficacy (2025-07-25, P07). The paper states the same in vivo efficacy across KRAS mutant and wild-type amplified xenografts. [R3995]

Donald W. Kufe, Harvard University

• C14 An anti-MUC1-C antibody-drug conjugate is highly effective against MRTX1133-resistant PDAC KRAS G12D models, and MUC1-C drives resistance to KRAS G12D inhibition via IFN type I signaling.
  • animal; verified against its paper; no independent support found in this corpus; source: Targeting KRAS Inhibitor–Resistant Pancreatic Cancer with an MUC1-C Antibody–Drug Conjugate (2025-10-14, P15)
  • Own paper:
    • claim: "MUC1-C drives resistance to KRAS G12D inhibition via IFN type I signaling" / paper: "an anti-M1C ADC is highly effective against MRTX1133-resistant PDAC KRAS G12D cell lines and patient-derived organoid and patient-derived xenograft models." — Targeting KRAS Inhibitor–Resistant Pancreatic Cancer with an MUC1-C Antibody–Drug Conjugate (2025-10-14, P15). The paper reports the same ADC efficacy against MRTX1133-resistant models and MUC1-C driving resistance via the IFN type I pathway. [R4000]

Niranjan Awasthi, Indiana University

• C20 MRTX1133, a KRAS G12D inhibitor, alone and combined with nab-paclitaxel/gemcitabine, inhibits KRAS G12D-mutant pancreatic cancer growth, with the combination giving tumor regression. Reported effect: Control 327 mm3; NPT-GEM 129 mm3; MRTX1133 56 mm3; combination -4 mm3 (tumor regression); no significant body weight change.
  • animal; verified against its paper; no independent support found in this corpus; source: Potent antitumor activity of the KRAS G12D inhibitor MRTX1133 in pancreatic cancer: Augmenting the nanoparticle-paclitaxel chemotherapy response. (2025-05-28, P14)
  • Own paper:
    • claim: "Control 327 mm3; NPT-GEM 129 mm3; MRTX1133 56 mm3; combination -4 mm3" / paper: "NPT-GEM reduced growth to 129 mm 3 , MRTX1133 reduced it to 56 mm 3 , and the combination resulted in tumor regression (-4 mm 3 )." — Potent antitumor activity of the KRAS G12D inhibitor MRTX1133 in pancreatic cancer: Augmenting the nanoparticle-paclitaxel chemotherapy response. (2025-05-28, P14). The abstract reports the same tumor growth values, regression with the combination, and no significant body weight change. [R4006]

Piro Lito, Cornell University

• C19 A natural product-inspired small molecule remodels cyclophilin A to form a neomorphic interface binding active KRAS G12C, inactivating oncogenic signaling and causing tumor regressions.
  • animal; verified against its paper; no independent support found in this corpus; source: Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS (2023-08-17, P13)
  • Own paper:
    • claim: "remodels cyclophilin A to form a neomorphic interface binding active KRAS G12C" / paper: "The resulting CYPA:drug:KRAS G12C tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models." — Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS (2023-08-17, P13). The paper reports the same cyclophilin A remodeling, neomorphic interface, inactivated signaling and tumor regressions. [R4005]

Adam R. Renslo, University of California, San Francisco

• C17 Oncogenic KRAS signaling induces ferrous iron accumulation, and a ferrous iron-activatable MEK inhibitor conjugate (FeADC) blocks MAPK in tumor cells while sparing normal tissue with better tolerability.
  • animal; verified against its paper; no independent support found in this corpus; source: Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS -driven tumors (2021-11-02, P24)
  • Own paper:
    • claim: "Oncogenic KRAS signaling induces ferrous iron accumulation" / paper: "We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation." — Ferrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS -driven tumors (2021-11-02, P24). The paper reports the same iron accumulation and an FeADC MEK inhibitor blocking MAPK while sparing normal tissues with better tolerability. [R4003]

Kian‐Huat Lim, Washington University in St. Louis

• C08 Combining MAPK inhibitors with trastuzumab deruxtecan (anti-HER2 antibody-drug conjugate) causes sustained tumour regression in most tested PDAC patient-derived xenografts without noticeable toxicity. Reported effect: Sustained tumour regression in most tested PDXs; combined ERK and HER inhibitors only slowed tumour growth without cytotoxic chemotherapy.
  • animal; verified against its paper; no independent support found in this corpus; source: Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer (2024-03-20, P23)
  • Own paper:
    • claim: "sustained tumour regression in most tested PDAC patient-derived xenografts without noticeable toxicity" / paper: "lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity." — Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer (2024-03-20, P23). The paper states the same combination, regression in most PDXs and no noticeable toxicity. [R4086]

Goutham Narla, University of Michigan

• C13 Combining the PP2A molecular glue RPT04402, which stabilizes PP2A-B56α heterotrimers, with a RAS/MAPK inhibitor overcomes resistance in KRAS-mutant NSCLC. Reported effect: Combination induced tumor regressions and extended median survival in xenografts; specific values not stated in abstract.
  • animal; verified against its paper; no independent support found in this corpus; source: A PP2A molecular glue overcomes RAS/MAPK inhibitor resistance in KRAS-mutant non–small cell lung cancer (2025-10-14, P20)
  • Own paper:
    • claim: "overcomes resistance in KRAS-mutant NSCLC" / paper: "In mouse xenografts, this combination induced tumor regressions, extended median survival, and delayed the onset of treatment resistance." — A PP2A molecular glue overcomes RAS/MAPK inhibitor resistance in KRAS-mutant non–small cell lung cancer (2025-10-14, P20). The paper reports the same PP2A molecular glue RPT04402 plus RAS/MAPK inhibitor overcoming resistance in KRAS-mutant NSCLC. [R3999]

Rong Zhou, University of Pennsylvania

• C07 Multiparametric MRI (DWI, DCE, MTR) detects early response and acquired resistance of pancreatic cancer to the KRAS G12D inhibitor MRTX1133. Reported effect: Significant ADC increase at 48h persisting to Day 7; greatly prolonged median survival in treated mice; no numeric values stated.
  • animal; verified against its paper; no independent support found in this corpus; source: Multimetric MRI Captures Early Response and Acquired Resistance of Pancreatic Cancer to KRAS Inhibitor Therapy (2025-04-21, P37)
  • Own paper:
    • claim: "detects early response and acquired resistance of pancreatic cancer to the KRAS G12D inhibitor MRTX1133" / paper: "Multiparametric MRI provides early biological insights of cancer and stromal response to KRASi treatment" — Multimetric MRI Captures Early Response and Acquired Resistance of Pancreatic Cancer to KRAS Inhibitor Therapy (2025-04-21, P37). The paper reports MRI metrics detecting early response and acquired resistance to MRTX1133 in pancreatic cancer models with increased ADC at 48h to Day7. [R3993]

Hiroaki Wakimoto, Harvard University

• C24 Combination of adagrasib and abemaciclib extended survival in an SW1573 orthotopic brain metastasis model, where neither monotherapy did, in KRAS-G12C NSCLC with CDKN2A loss. Reported effect: Combination caused about 10% body weight loss at adagrasib 75 mg/kg twice daily plus abemaciclib 50 mg/kg daily; abemaciclib monotherapy ineffective in H2122 model.
  • animal; verified against its paper; no independent support found in this corpus; source: Combination therapy of adagrasib and abemaciclib in non-small cell lung cancer brain metastasis models genomically characterized by KRAS-G12C and homozygous loss of CDKN2A (2025-05-02, P08)
  • Own paper:
    • claim: "extended survival in an SW1573 orthotopic brain metastasis model, where neither monotherapy did" / paper: "Notably, combination treatment, but neither monotherapy, extended animal survival in the SW1573 model." — Combination therapy of adagrasib and abemaciclib in non-small cell lung cancer brain metastasis models genomically characterized by KRAS-G12C and homozygous loss of CDKN2A (2025-05-02, P08). The paper reports the same survival result in SW1573, about 10% body weight loss at the stated doses, and ineffective abemaciclib monotherapy in H2122. [R4010]

Chad Victor Pecot, University of North Carolina at Chapel Hill

• C22 A custom siRNA oligonucleotide (EFTX-D1) preferentially reduces mutant KRAS mRNA and protein versus wild-type and impairs proliferation of KRAS mutant cancer cell lines.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Silencing of Oncogenic KRAS by Mutant-Selective Small Interfering RNA (2021-02-04, P34)
  • Own paper:
    • claim: "preferentially reduces mutant KRAS mRNA and protein versus wild-type and impairs proliferation of KRAS mutant cancer cell lines" / paper: "EFTX-D1 preferentially reduced the mutant KRAS sequence versus wild-type at the levels of both transcription and translation" — Silencing of Oncogenic KRAS by Mutant-Selective Small Interfering RNA (2021-02-04, P34). The paper reports the same preferential mutant KRAS reduction and impaired proliferation of KRAS mutant cell lines. [R4008]
• C02 An EGFR-directed siRNA molecule (EFTX-G12V) is highly selective for KRAS G12V and shows improved therapeutic activity over pan-KRAS targeting.
  • not stated; verified against its paper; no independent support found in this corpus; source: A first-in-class EGFR-directed KRAS G12V selective inhibitor (2025-06-19, P38)
  • Own paper:
    • claim: "is highly selective for KRAS G12V and shows improved therapeutic activity over pan-KRAS targeting" / paper: "an EGFR-directed RNAi molecule (EFTX-G12V) is highly selective for KRAS G12V and exhibits improved therapeutic activity over pan-KRAS targeting" — A first-in-class EGFR-directed KRAS G12V selective inhibitor (2025-06-19, P38). The paper states the same selectivity and improved activity over pan-KRAS targeting for EFTX-G12V. [R3988]

Shohei Koide, New York University

• C05 Adagrasib-KRAS(G12C) peptide/HLA complexes created by covalent drug binding can be targeted by selective antibodies in bispecific T cell engagers that kill adagrasib-treated, resistant lung cancer cells.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Generation of actionable, cancer-specific neoantigens from KRAS(G12C) with adagrasib (2025-07-30, P10)
  • Own paper:
    • claim: "can be targeted by selective antibodies in bispecific T cell engagers that kill adagrasib-treated, resistant lung cancer cells" / paper: "The antibodies in a bispecific T cell engager format killed adagrasib-resistant lung cancer cells upon adagrasib treatment." — Generation of actionable, cancer-specific neoantigens from KRAS(G12C) with adagrasib (2025-07-30, P10). The paper reports the same bispecific T cell engager killing of adagrasib-resistant lung cancer cells. [R3991]
• C11 A monobody, 12VC1, recognizes active KRAS(G12V) and KRAS(G12C) up to 400-fold more tightly than wild-type KRAS and inhibits RAS signaling; fused to VHL it selectively degrades KRAS mutants. Reported effect: Up to 400-times tighter binding than wild-type KRAS; potent inhibition of ERK activation and proliferation in vitro and in mouse xenografts.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Selective and noncovalent targeting of RAS mutants for inhibition and degradation (2021-05-11, P28)
  • Own paper:
    • claim: "recognizes active KRAS(G12V) and KRAS(G12C) up to 400-fold more tightly than wild-type KRAS" / paper: "12VC1 that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS." — Selective and noncovalent targeting of RAS mutants for inhibition and degradation (2021-05-11, P28). The paper reports the same monobody binding, 400-times tighter than wild-type, and VHL-fusion degradation. [R3997]

Samy O. Meroueh, Indiana University

• C03 Aryl sulfonyl fluoride fragment 1 (SOF-436) covalently modifies KRAS at Tyr-64 (major) and Tyr-71 (minor), inhibiting SOS1-mediated nucleotide exchange and RAF binding.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Small‐Molecule KRAS Inhibitors by Tyrosine Covalent Bond Formation (2025-03-18, P25)
  • Own paper:
    • claim: "covalently modifies KRAS at Tyr-64 (major) and Tyr-71 (minor)" / paper: "Tyr‐64 is the major reaction site of 1 (SOF‐436), although minor reaction at Tyr‐71 is also observed." — Small‐Molecule KRAS Inhibitors by Tyrosine Covalent Bond Formation (2025-03-18, P25). The paper gives the same major and minor tyrosine reaction sites for SOF-436. [R3989]

Adam Joel Bass, Harvard University

• C21 SHP2 inhibition combined with pan-ERBB kinase inhibition or CDK4/6 inhibition shows enhanced cytotoxicity in KRAS-amplified gastroesophageal adenocarcinoma, more so than in KRAS-mutant tumors for CDK4/6 combination.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Developing SHP2-based combination therapy for KRAS-amplified cancer (2023-02-07, P19)
  • Own paper:
    • claim: "more so than in KRAS-mutant tumors for CDK4/6 combination" / paper: "with greater efficacy of this combination in KRAS-amplified, compared with KRAS-mutant, tumors." — Developing SHP2-based combination therapy for KRAS-amplified cancer (2023-02-07, P19). The paper reports the same SHP2 plus pan-ERBB or CDK4/6 combinations in KRAS-amplified GEA with greater CDK4/6 combination efficacy than in KRAS-mutant tumors. [R4007]

Shahana S. Mahajan, Cornell University

• C23 Daraxonrasib, a pan-KRAS inhibitor, selectively attenuated proliferation and migration of KRAS mutant osteosarcoma cells by halting AKT/ETS1 signaling and suppressing MMP1 and MMP9 expression.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Daraxonrasib, a pan-RAS inhibitor, selectively inhibits osteosarcomas with activated KRAS by halting AKT signaling and matrix metalloprotease activity (2025-08-08, P36)
  • Own paper:
    • claim: "selectively attenuated proliferation and migration of KRAS mutant osteosarcoma cells by halting AKT/ETS1 signaling and suppressing MMP1 and MMP9 expression" / paper: "Daraxonrasib selectively attenuated the proliferation and migratory ability of KRAS mutant HOS-143B cells without affecting KRAS wild-type controls." — Daraxonrasib, a pan-RAS inhibitor, selectively inhibits osteosarcomas with activated KRAS by halting AKT signaling and matrix metalloprotease activity (2025-08-08, P36). The paper reports the same selective effects with AKT/ETS1 inhibition and suppressed MMP9 and MMP1. [R4009]

Ralph Weissleder, Harvard University

• C16 A two-step approach using an ARS-1323 alkyne for target binding followed by in situ click chemistry with picolyl azide Alexa Fluor 647 can image mutant KRAS G12C directly in cells.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Small Molecule Imaging Agent for Mutant KRAS G12C (2021-03-12, P02)
  • Own paper:
    • claim: "using an ARS-1323 alkyne for target binding followed by in situ click chemistry with picolyl azide Alexa Fluor 647" / paper: "It is shown that this approach can be used to image mutant KRAS G12C directly in cells." — Small Molecule Imaging Agent for Mutant KRAS G12C (2021-03-12, P02). The paper reports the same two-step ARS-1323 alkyne and picolyl azide Alexa Fluor 647 imaging of KRAS G12C in cells. [R4002]

Karen M. Cichowski, Harvard University

• C01 Combined EZH2 inhibitors and RAS pathway inhibitors cooperatively suppress WNT signaling, drive differentiation, and induce BMF-mediated apoptosis, killing KRAS-mutant colorectal cancer cells. Reported effect: Described as dramatic tumor regression in vivo and durable regression; no numeric effect sizes stated in abstract.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS - Mutant Colorectal Cancers (2024-08-09, P16)
  • Own paper:
    • claim: "cooperatively suppress WNT signaling, drive differentiation, and induce BMF-mediated apoptosis" / paper: "Combined EZH2 and RAS pathway inhibitors kill KRAS-mutant colorectal cancer cells and promote durable tumor regression in vivo." — Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS - Mutant Colorectal Cancers (2024-08-09, P16). The paper reports the same EZH2 plus RAS pathway inhibitor combination killing KRAS-mutant colorectal cancer cells with durable regression. [R3987]

Joan T. Garrett, University of Cincinnati

• C04 Co-targeting KRASG12D and HER3 or the HER family, using MRTX1133 with pan-HER inhibitors or a HER3 antibody-drug conjugate, is a potential therapeutic strategy in colorectal cancer. Reported effect: Synergistic and additive reductions in cell growth with pan-HER inhibitors plus MRTX1133; further reduced viability with KRASG12D inhibitor plus HER3 ADC; no numeric values stated.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Co-targeting KRASG12D and the HER family is efficacious in colorectal cancer (2025-02-01, P41)
  • Own paper:
    • claim: "using MRTX1133 with pan-HER inhibitors or a HER3 antibody-drug conjugate, is a potential therapeutic strategy in colorectal cancer" / paper: "co-targeting both KRASG12D and HER3, whether directly or indirectly, is a potential therapeutic strategy in CRC patients." — Co-targeting KRASG12D and the HER family is efficacious in colorectal cancer (2025-02-01, P41). The paper proposes the same co-targeting strategy in colorectal cancer with MRTX1133, pan-HER inhibitors and a HER3 antibody-drug conjugate. [R3990]

Nagavarakishore Pillarsetty, Cornell University

• C06 A radioiodinated sotorasib analog, [124I]I-Sotorasib, can target KRAS G12C mutant tumor lesions for PET imaging.
  • not stated; verified against its paper; no independent support found in this corpus; source: [Preclinical Evaluation of [ 124 I]-Sotorasib for the Imaging of Kirsten Rat Sarcoma G12C Mutant Tumors](https://doi.org/10.1021/acsptsci.4c00425) (2024-11-21, P31)
  • Own paper:
    • claim: "can target KRAS G12C mutant tumor lesions for PET imaging" / paper: "an [ 124 I]I-Sotorasib analog in targeting G12C mutant tumor lesions using PET imaging." — [Preclinical Evaluation of [ 124 I]-Sotorasib for the Imaging of Kirsten Rat Sarcoma G12C Mutant Tumors](https://doi.org/10.1021/acsptsci.4c00425) (2024-11-21, P31). The paper evaluates the same radioiodinated sotorasib analog for PET imaging of KRAS G12C tumor lesions. [R3992]

Framed read (unvalidated: one model's synthesis of the records above)

Claim that carries the most weight: C14. Several other claims on the sheet (C04, C07, C13) assume that resistance to direct KRAS inhibition emerges and must be overcome or detected, and C14 is the claim that names a specific resistance mechanism and a drug that targets it. Its only record (R4000) comes from the claim's own paper, so the rest of the sheet leans on a result no independent paper in this pack addresses.

What would have to hold:

• The anti-M1C ADC effect in MRTX1133-resistant models must hold outside the originating paper; no record covers an independent paper for this (R4000 is not independent).
• MUC1-C must actually drive resistance via IFN type I signaling; R4000 quotes only ADC efficacy, so no record covers the mechanistic half of the claim directly.
• Resistance to KRAS inhibition must be a common, clinically relevant outcome rather than a model artifact; R3993 reports acquired resistance only in the claim's own paper, and no record covers patients.
• The efficacy seen in cell lines, organoids and xenografts must carry over to humans; the only human-tier records (R3996, R3998) concern different agents and do not address it.

Questions a data room would have to answer:

• (C14) Which MRTX1133-resistant PDAC cell lines, organoids and xenografts were used, how was resistance established, and were the anti-MUC1-C ADC results repeated in more than one independent model?
• (C14) What data show that MUC1-C causally drives resistance through IFN type I signaling, such as knockdown or rescue experiments, rather than correlating with it?
• (C07) Were the multiparametric MRI response and acquired-resistance readouts validated against histology or an independent cohort, and what did the untreated and resistant tumors look like on each MRI parameter?
• (C04) Were the MRTX1133 plus pan-HER inhibitor and HER3 ADC combinations tested beyond cell viability, and is the synergy reproducible across colorectal lines with different HER3 expression?
• (C20) How many animals per arm, what variance, and what statistical test support the reported tumor volume differences between MRTX1133, the chemotherapy doublet and the combination?
• (C13) What is the toxicity and dosing profile of the PP2A molecular glue plus RAS/MAPK inhibitor combination in the xenograft studies, and how long did regressions last after treatment stopped?
• (C10) What safety, dose and response data from the phase 1 trial of oral LY3962673 exist beyond the design description, and when would they be disclosed?

Cannot say:

• Whether any claim on the sheet is reproduced by another group; every record comes from the claim's own paper and none is independent.
• Whether the preclinical results translate to patients, since only two claims carry a human evidence tier and one of those is a trial design and the other a single case report.
• How large any effect is for claims whose records state no numbers, such as C01, C04, C07 and C13.
• Which lab is best positioned commercially; the records say nothing about intellectual property, funding, team or company formation.
• Whether the claims interact, for example whether the resistance mechanisms in C05, C14 and C24 overlap, since no record compares them.

What was not shown

• Claims with no checked record: none.
• Records proposed: 25; refused by code (a quote not found, or a number of the reader's own): 1; removed by the checker: 0.
• Papers without an abstract, not read: 0.

Run record

• run: sci-a6ce265218; reader arm: B1R; spec: sci-0.1; rank rule: scirank-v1
• reader prompt sha256: c04daba6743bf488eaeb3427cec02860a257d2c06ef9f58cf307195206620e03; model: claude-sonnet-5-5, medium effort
• extraction: claude-haiku-5-5, prompt extract_v0.3; no human has verified it