MRTX1257 / BMS - LARVOL DELTA

Functional genomics studies identify determinants of response vs. resistance to pharmacological inhibitors of KRAS in multiple myeloma (ASH 2025) - "We evaluated Rasinhibitors in preclinical models of MM, with emphasis on genome-scale CRISPR studies to define themolecular determinants of response and resistance to these agents.We studied selective inhibitors of KRAS G12C (MRTX-1257) or G12D (MRTX-1133) mutants; the broaderspectrum mutant-KRAS inhibitor BI-2865; or the tricomplex pan-Ras inhibitor RMC-6236. Notably, even MM cells with the same KRASmutation can display distinct "resistomes", highlighting the complex functional genomic landscapeunderlying Ras inhibitor responses. We envision that these results will inform personalized uses of Rasinhibitors in future clinical studies in MM."

Genomic study • Hematological Malignancies • Multiple Myeloma • Solid Tumor • ABCB1 • DUSP6 • EGFR • FGFR3 • IL6 • KEAP1 • KRAS • LZTR1 • NRAS • PPIA

Targeting Mutant KRAS with Novel Mutant-Specific Pharmacological Inhibitors: Activity Against Myeloma and Other Lymphoid Malignant Cells and Molecular Mechanisms of Resistance (ASH 2023) - "We assessed the activity of novel G12C- (MRTX1257) and G12D- (MRTX1133) specific pharmacological KRAS inhibitors against 2 MM lines with G12C (KHM1B, XG7) and 2 with G12D (KARPAS620, KP6) KRAS mutations; as well as the G12D mutant KOPN-8 (B-ALL) and CCRF-CEM (T-ALL) lines...melphalan, bortezomib, pomalidomide, trametinib) caused in some cases supra-additive effects, but – more importantly – showed no antagonism with any combination...This study also provides functional evidence about genes and molecular pathways that regulate MM cell sensitivity vs. resistance to KRAS inhibitors. These results create a framework for ongoing and future efforts to translate the use of KRAS inhibitors into clinical studies for MM and other lymphoid malignancies."

Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • ANXA5 • DUSP6 • EGFR • ETV4 • ETV5 • KRAS

Functional Genomics Studies Decipher the Genetic Perturbations and Unravel Mechanisms of Response/Resistance upon Mutant-Specific KRAS Inhibition in Multiple Myeloma (ASH 2024) - "METHODS : We performed a total of 11 genome-scale CRISPR gene activation or CRISPR gene editing (knockout, KO) studies in 5 MM lines with distinct KRAS point mutations (KHM-1B and XG-7 [G12C]; KARPAS-620 and KP-6 [G12D]; or MM.1S [G12A]) after treatment with specific KRAS inhibitors (MRTX-1133, MRTX-1257, BI-2865, RMC-6236) in clinically achievable concentration ranges (as used in patients with solid tumors). These compounds exhibit potent and specific activity against MM cells with the respective KRAS mutations, but our functional studies point to individual lines, even those harboring the same KRAS mutation, exhibiting their own distinct "resistome" against these inhibitors. These results underscore the complex functional genomics of MM cell sensitivity vs. resistance to KRAS inhibitors and have implications for the choice of potential combination partners of these inhibitors in future preclinical or clinical studies."

Genomic study • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • ANXA5 • DUSP6 • EGFR • ETV4 • ETV5 • KEAP1 • KRAS • LZTR1

Specific inhibitor to KRASG12C induces tumor-specific immunity and synergizes with oncolytic virus for enhanced cancer immunotherapy. (PubMed, J Immunother Cancer) - "Small molecule inhibitors of KRASG12C are novel inducers of tumor-specific immunity, and a unique triple combination regimen is highly efficacious through elicited potent antitumor immunity for KRASG12C cancers."

IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • CTLA4 • GZMB • HAVCR2 • IFNG • KRAS

CD24 promotes development of KRAS-mutant lung adenocarcinoma and response to KRAS-targeted therapy (AACR 2025) - "Analysis of publicly available datasets showed that KRASG12C inhibitor MRTX1257 also increased Cd24a expression in mouse tumor cells with KRAS p.G12C mutations. In syngeneic mice with KrasG12C/+; Tp53R172H/+ KM-LUAD cells, sotorasib treatment enhanced CD24 protein levels in tumors compared to controls...Syngeneic mice treated with MRTX1133 and anti-CD24 antibodies showed greater KM-LUAD reduction than single agents or controls...Similarly, combining KRASG12C inhibitor adagrasib with anti-CD24 antibody in syngeneic mice reduced KM-LUAD growth more than single treatments or controls. Our findings demonstrate that CD24 drives KM-LUAD progression from its earliest stages and contributes to adaptive resistance to KRAS inhibition. Targeting CD24 in combination with KRAS inhibitors, represents a promising strategy for treating and intercepting KM-LUAD."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD24 • GPRC5A • KRAS

CRISPR-based functional genomics studies identify mechanisms of multiple myeloma (MM) cell response to vs. resistance against novel pharmacological mutant-specific KRAS inhibitors. (IMW 2024) - " The KRAS G12D-mutant MM cell lines KP-6 and KARPAS620 and the KRAS G12C-mutant lines XG-7 and KHM-1B were treated with the small molecule KRAS inhibitors MRTX1133 (G12D-specific) and MRTX1257 (G12C-specific), respectively, in different concentrations within the clinically achievable concentration range in patients with solid tumors. Mutant-specific KRAS G12C and G12D inhibitors show strong in vitro activity in MM cells with these mutations. CRISPR KO or gene activation studies provide functional insights into the pharmacological inhibition of KRAS in MM, identifying potential targets which regulate the response vs. resistance of MM cells to KRAS inhibitors."

Genomic study • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • EGFR • KRAS • LZTR1

KRAS inhibition using MRTX1257: a novel radio-sensitizing partner. (PubMed, J Transl Med) - "This work is the first to demonstrate in vitro as in vivo the radio-sensitizing effect of MRTX1257, a potent KRAS inhibitor compatible with oral administration, in CT26 KRAS mutated cell lines and tumors. This is a first step towards the use of new combinatorial strategies using KRAS inhibitors and RT in KRAS mutated tumors, which are the most represented in NSCLC with 14% of patients harboring this mutational profile."

IO biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CDK1 • KRAS • NRAS

KRAS G12C inhibition using MRTX849: A novel radio-sensitizing partner (ESMO 2023) - "Legal entity responsible for the study The authors. Expression of PD-L1 was reduced within tumor and myeloid cells, illustrating TME polarization towards a pro-inflammatory phenotype following the combination. Conclusions This work constitutes a first step towards new combinatorial approaches involving RT and MRTX1257 in KRAS G12C mutated cancers, with the aim of providing new therapeutic strategies."

IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • KRAS • NRAS • PD-L1

Mutant-specific pharmacological inhibition of KRAS in multiple myeloma and functional genomics studies to identify mechanisms regulating myeloma cell response vs. resistance to KRAS inhibition. (IMW 2023) - "MRTX1257 predominantly reduced proliferation of XG7 cells, whereas MRTX1133 led to potent cell death induction of KARPAS620 and KP6 cells. Combinations of MRTX1257 with investigational or established anti-MM drugs, including melphalan, bortezomib or pomalidomide, led to no antagonism and in some cases – including combination with MEKi trametinib – caused supra-additive effects... This study documents mutant-specific activity of KRAS G12C and G12D inhibitors in MM cells and provides functional insights into the pharmacological inhibition of KRAS in MM. Ongoing in vitro and in vivo studies are examining the targeting of genes/pathways associated with escape from KRAS inhibition, as a framework for future efforts to improve the rates, depth and durability of responses to KRAS inhibition in MM."

Genomic study • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • DUSP6 • EGFR • ETV4 • ETV5 • KRAS

Evaluation of KRAS inhibitor responses in novel murine KRAS lung cancer cell line models. (PubMed, Front Oncol) - "The three lines exhibit similar in vitro sensitivities to KRAS inhibitors (MRTX-1257, MRTX-849, AMG-510), but distinct in vivo responses to MRTX-849 ranging from progressive growth with orthotopic LLC-NRAS KO tumors to modest shrinkage with mKRC.1 tumors. All three cell lines exhibited synergistic in vitro growth inhibition with combinations of MRTX-1257 and the SHP2/PTPN11 inhibitor, RMC-4550...Notably, single-agent MRTX-849 activity in mKRC.1 tumors and the combination response in LLC-NRAS KO tumors was lost when the experiments were performed in athymic nu/nu mice, supporting a growing literature demonstrating a role for adaptive immunity in the response to this class of drugs. These new models of murine KRAS mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRAS inhibitors."

Journal • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • NRAS • PTPN11

[PREPRINT] Evaluation of KRASG12C Inhibitor Responses in Novel Murine KRASG12C Lung Cancer Cell Line Models (bioRxiv) - “To provide models for further preclinical improvement of these inhibitors, we generated three novel murine KRASG12C-driven lung cancer cell lines….The three lines exhibit similar in vitro sensitivities to KRASG12C inhibitors (MRTX-1257, AMG-510), but distinct in vivo responses to MRTX-849 ranging from progressive growth with orthotopic LLC-NRAS KO tumors to marked shrinkage with mKRC.1 tumors. All three cell lines exhibited synergistic in vitro growth inhibition with MRTX-1257 and the SHP2 inhibitor, RMC-4550 and the MRTX-849/RMC-4550 combination yielded tumor shrinkage in orthotopic LLC-NRAS KO tumors propagated in syngeneic mice….These new models of murine KRASG12C mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRASG12C inhibitors.”

Preclinical • Preprint • Oncology

Inhibitor of the Nuclear Transport Protein XPO1 Enhances the Anticancer Efficacy of KRAS G12C Inhibitors in Preclinical Models of KRAS G12C-Mutant Cancers. (PubMed, Cancer Res Commun) - "FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC)...In this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for cancer patients that do not respond or develop resistance to KRAS G12C inhibitor treatment."

IO biomarker • Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • XPO1

[VIRTUAL] Inhibition of nuclear transport protein XPO1 potentiates the effect of KRAS G12C inhibitors (AACR 2021) - "In this study, we have tested two potent KRASG12C inhibitors, MRTX1257 and AMG510, on PDAC and NSCLC cell lines both as single agents and also in combination with nuclear transport inhibitor, Selinexor (KPT-330/XPOVIO). Cell growth inhibition was determined by MTT assay. In conclusion, we have demonstrated that the inhibitor of nuclear transport protein XPO1 has the ability to potentiate the anticancer activity of KRASG12C inhibitors in in vitro preclinical models of PDAC and NSCLC."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

RAS-pathway inhibitors (Sotorasib, MRTX-1257, TNO-155, BI-3406) in a Complex Spheroid Combination Screen with PDMR Cell Lines (AACR 2022) - "The most successful combination was TNO-155 plus ipatasertib which resulted in more than 1-log of cell kill in 9 of 20 lines including the 5 KRAS G12C mutant lines. Venetoclax in combination with the RAS pathway inhibitors was active in 4 of the 5 KRAS G12C lines as was the combination of sapanisertib and TNO-155...This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E."

Preclinical • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Patient-derived organoid drug responses corroborate known target-drug interactions for selected anticancer agents (AACR 2022) - "The approved and investigational agents were selected to target specific genetic variants and pathways: KRAS G12C covalent inhibitors (sotorasib and MRTX-1257), RAS pathway inhibitors (BAY-293, BI-3406 and TNO-155), BRAF V600E/K inhibitors (dabrafenib and encorafenib), ABCB1 substrates (paclitaxel, doxorubicin, 5-FU, AZD-1775, and SN-38), and ABCB1 non-substrates (gemcitabine and trametinib)...This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I."

Clinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • ABCB1 • KRAS

Application of NanoBRET target engagement cellular assay for measurement of inhibitor binding to wild type and mutant RAS in live cells (AACR 2022) - "In addition, we are able to confirm the signaling inhibition of downstream phospho-ERK1/2 by KRAS (G12C)-specific inhibitors AMG 510 (Sotorasib), ARS-1620, MRTX849, and MRTX1257 in MIA PaCa-2 pancreas and SW837 colon cancer cells bearing KRAS (G12C) mutation by Western blot assay. Our results suggest NanoBRETTM TE cellular assay can serve as a great tool to facilitate RAS pathway drug discovery against human cancers."

Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HRAS • KRAS

[VIRTUAL] Combination screening of KRASG12C specific inhibitors with other targeted therapies in patient-derived multicellular tumor spheroids (AACR 2021) - "The pancreatic cancer cell line 323965-272-R-J2 carrying a KRASG12C variant exhibited an enhanced sensitivity to the combination of the mTOR inhibitor everolimus and a low concentration of either AMG-510 or MRTX-1257...Similarly, combining the mTOR kinase inhibitor sapanisertib, which blocks both mTORC1 and mTORC2 activities, with MTRX-1257 also led to a notable reduction in cell viability in all three KRASG12C-containing cell lines. In the KRASG12C variant melanoma cell line 299254-011-R-J1, targeting of the upstream receptor tyrosine kinase FGFR with erdafitinib in combination with the KRASG12C inhibitors produced greater than additive cell killing over the concentration range from 0.1 to 10 µM. Lastly, both KRASG12C inhibitors and abemaciclib, demonstrated additive to greater than additive cytotoxicity in the pancreatic cancer cell line 323965-272-R-J2, but this outcome was not observed with the CDK4/6 inhibitor, palbociclib, or in the other KRASG12C variant cell..."

Clinical • Gastrointestinal Cancer • Melanoma • Oncology • Pancreatic Cancer • Solid Tumor • FGFR • KRAS

Validated HPLC-MS/MS method for quantitation of AMG 510, a KRAS G12C inhibitor in a small volume of mouse plasma and its application to a pharmacokinetic study in mice. (PubMed, Biomed Chromatogr) - "AMG 510 and the IS (MRTX-1257) were extracted from mouse plasma using tert-butyl methyl ether and chromatographed using an isocratic mobile phase (0.2% formic acid:acetonitrile; 25:75, v/v) at a flow-rate of 0.65 mL/min on an Atlantis dC column. AMG 510 was demonstrated to be stable under the tested storage conditions. This novel method has been applied to a pharmacokinetic study in mice."

Journal • PK/PD data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

[VIRTUAL] Targeting oncogenic signalling pathways to modulate the lung cancer immune microenvironment (AACR-NCI-EORTC 2020) - "Subsequent inhibition of oncogenic signalling using the KRAS-G12C inhibitor MRTX1257, led to profound changes in immune activation state and composition within the tumours. Tumour cell intrinsic changes in expression of chemokines and cytokines, antigen presentation and interferon pathway activation, altogether relieve immune suppression mechanisms. In conclusion, there will be an excellent opportunity to exploit the liberation of the anti-tumour immune response upon KRAS-G12C inhibition in lung cancer."

IO Biomarker • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

[VIRTUAL] Targeting oncogenic signalling pathways to modulate the lung cancer immune microenvironment (AACR-NCI-EORTC 2020) - "Subsequent inhibition of oncogenic signalling using the KRAS-G12C inhibitor MRTX1257, led to profound changes in immune activation state and composition within the tumours. Tumour cell intrinsic changes in expression of chemokines and cytokines, antigen presentation and interferon pathway activation, altogether relieve immune suppression mechanisms. In conclusion, there will be an excellent opportunity to exploit the liberation of the anti-tumour immune response upon KRAS-G12C inhibition in lung cancer."

IO Biomarker • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

[VIRTUAL] Inhibiting adenosine signaling and KRAS enhances the effect of α-PD-1 therapy in a KRASG12C/TP53R172H/+ pancreatic cancer model (AACR-II 2020) - "C57BL/6J mice bearing established KP4662-G12C (KRASG12C/TP53R172H/+) tumors (at least 150 mm3) were treated as indicated: A1421 (CD73i; 30 mg/kg/day, s.c.), anti-PD1 (Clone RMP 1-14; 10 mg/kg; twice per week, i.p), and MRTX-1257 (KRASi, 100 mg/kg/day, p.o.)... Here, we show that direct inhibition of mutant KRAS in pancreatic cancer models yields complex immunomodulatory effects. While antigen presentation pathways are transcriptionally upregulated and the expression of immunosuppressive chemokine is reduced, KRAS inhibition also reprograms nucleotide metabolism leading to elevated levels of ADO. These findings suggest that co-targeting mutant KRAS and adenosine signaling may enhance immunotherapy against pancreatic cancer and potentially other KRAS driven malignancies."

IO Biomarker • Preclinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD73 • KRAS

[VIRTUAL] Focal adhesive kinase inhibitor IN10018 sensitizes KRAS mutant cancer and overcomes drug resistance of KRAS G12C inhibition (AACR-II 2020) - "Recently, KRAS G12C inhibitors like AMG510, MRTX849, and MRTX1257 were developed and exhibited promising therapeutic outcomes targeting the mutation. IN10018 significantly decreased the upregulated FAK Y397 phosphorylation in the combination treatments, underlying the mechanism of synergy between the two inhibitors. Our results indicate that KRAS G12C cancer patients can be better treated by the combination of IN10018 with KRAS G12C inhibitor."

Late-breaking abstract • Oncology • KRAS