Glimmers of hope for targeting oncogenic KRAS-G12D

Tang, Daolin; Kang, Rui

doi:10.1038/s41417-022-00561-3

Cited by 18 publications

(15 citation statements)

References 26 publications

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“…To this date published data regarding MRTX1133 showed efficacy against only KRAS G12D and effect on T cells. (30, 34–39)…”

Section: Discussionmentioning

confidence: 99%

Synergistic anti-tumor activity, reduced pERK, and immuno-stimulatory cytokine profiles with 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in CRC and pancreatic cancer cells independent of G12D mutation

Tajiknia,

Pinho-Schwermann,

Srinivasan

et al. 2023

Preprint

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KRAS mutations occur in ~40-50% of mCRC and are associated with aggressive disease that is refractory to anti-EGFR therapies. Pancreatic cancer harbors ~90% KRAS driver gene mutation frequency. Small molecules targeting KRAS G12C gained FDA approval for KRAS G12C-mutated NSCLC. ONC212, a fluorinated imipridone with nM anti-cancer activity has preclinical efficacy against pancreatic cancer and other malignancies. MRTX1133, identified as a noncovalent selective KRAS G12D inhibitor that suppresses G12D signaling by binding to the switch II pocket thereby inhibiting protein-protein interactions. We investigated cell viability, drug synergies, pERK suppression and cytokine, chemokine or growth factor alterations following treatment with 5-Fluorouracil (5-FU) or ONC212 plus MRTX1133 in 6 human CRC and 4 human pancreatic cancer cell lines. IC50 sensitivities ranged from 7 to 12 microM for 5-FU, 0.2-0.8 microM for ONC212, and >100 nM to >5,000 nM for MRTX1133 (G12D N=4: LS513 >100, HPAF-II >1,000, SNUC2B >5,000, PANC-1 >5,000). For non-G12D, the range of IC50 for MRTX1133 was >1,000 to >5,000 nM for CRC lines with G12V, G13D, or WT KRAS (N=7). Synergies between MRTX1133 plus 5-FU or ONC212 were observed regardless of KRAS G12D mutation with combination indices of <0.5 indicating strong synergy. Observed synergies were greater with MRTX1133 plus ONC212 compared to MRTX1133 plus 5-FU. pERK was suppressed with mutant but not wild-type KRAS at nM MRTX1133 doses. Immunostimulatory profiles included reduction in IL8/CXCL8, MICA, Angiopoietin 2, VEGF and TNF-alpha and increase in IL-18/IL-1F4 with MRTX treatments and combinations. Our studies reveal preclinical activity of MRTX1133 alone or synergies when combined with 5-FU or ONC212 against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation. The results suggest that KRAS G12V and KRAS G13D should be further considered in clinical trials including combination therapies involving MRTX1133 and 5-FU or ONC212.

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“…To this date published data regarding MRTX1133 showed efficacy against only KRAS G12D and effect on T cells. (30, 34–39)…”

Section: Discussionmentioning

confidence: 99%

Synergistic anti-tumor activity, reduced pERK, and immuno-stimulatory cytokine profiles with 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in CRC and pancreatic cancer cells independent of G12D mutation

Tajiknia,

Pinho-Schwermann,

Srinivasan

et al. 2023

Preprint

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“…Those compounds for which the IC50 value was not reported were removed from the dataset. The compounds were labeled as active or inactive based on the IC50 value of the standard compound MRTX1133 (6.1 nM) [21]. The active and inactive compounds in the dataset were denoted by the labels 1 and 0, respectively.…”

Section: Preparation Of Datasetmentioning

confidence: 99%

“…MRT1133 was considered as the standard compound. The standard compound's IC50 value was found to be 6.1 nM [21]. Based on the IC50 value, the compounds were divided into active and inactive categories.…”

Section: Dataset Preparationmentioning

confidence: 99%

In Silico Prediction of New Inhibitors for Kirsten Rat Sarcoma G12D Cancer Drug Target Using Machine Learning-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulation Approaches

Ajmal,

Danial,

Zulfat

et al. 2024

Pharmaceuticals

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Single-point mutations in the Kirsten rat sarcoma (KRAS) viral proto-oncogene are the most common cause of human cancer. In humans, oncogenic KRAS mutations are responsible for about 30% of lung, pancreatic, and colon cancers. One of the predominant mutant KRAS G12D variants is responsible for pancreatic cancer and is an attractive drug target. At the time of writing, no Food and Drug Administration (FDA) approved drugs are available for the KRAS G12D mutant. So, there is a need to develop an effective drug for KRAS G12D. The process of finding new drugs is expensive and time-consuming. On the other hand, in silico drug designing methodologies are cost-effective and less time-consuming. Herein, we employed machine learning algorithms such as K-nearest neighbor (KNN), support vector machine (SVM), and random forest (RF) for the identification of new inhibitors against the KRAS G12D mutant. A total of 82 hits were predicted as active against the KRAS G12D mutant. The active hits were docked into the active site of the KRAS G12D mutant. Furthermore, to evaluate the stability of the compounds with a good docking score, the top two complexes and the standard complex (MRTX-1133) were subjected to 200 ns MD simulation. The top two hits revealed high stability as compared to the standard compound. The binding energy of the top two hits was good as compared to the standard compound. Our identified hits have the potential to inhibit the KRAS G12D mutation and can help combat cancer. To the best of our knowledge, this is the first study in which machine-learning-based virtual screening, molecular docking, and molecular dynamics simulation were carried out for the identification of new promising inhibitors for the KRAS G12D mutant.

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“…In detail, this inhibitor showed tumor regression >30% in 73% (8/11) of KRAS G12D-mutated PDAC cell lines and patient-derived xenografts (PDX) [ 40 ]. MRTX1133 is currently in first clinical studies labeled “MRTX1133 in Patients With Advanced Solid Tumors Harboring a KRAS G12D Mutation” (NCT05737706) [ 41 , 42 ]. This is a Phase 1/2 multicenter study checking the safety and antitumor activity of MRTX1133 in patients with KRAS G12D mutant solid tumors.…”

Section: Introductionmentioning

confidence: 99%

“…MRTX1133 shows low affinity against wild-type KRAS protein but may reactivate upstream signaling events by upregulating the expression and phosphorylation of EGFR and HER2 [ 42 ]. Accordingly, the combination of MRTX1133 with the EGFR inhibitors Cetuximab or Afatinib have been reported to show increased anticancer activity in xenograft models [ 48 , 49 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting KRAS in pancreatic cancer

STICKLER,

RATH,

HAMILTON

2024

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Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies. The Kirsten rat sarcoma virus (KRAS) oncogene is mutated in up to 90% of all pancreatic ductal adenocarcinomas (PDACs) and constitutes an attractive target for therapy. However, the most common KRAS mutations in PDAC are G12D (44%), G12V (34%) and G12R (20%) that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer. KRAS G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%–3% of PDAC. Recently, the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development. The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor (GEF) Son of Sevenless 1 that drives KRAS. These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.

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Glimmers of hope for targeting oncogenic KRAS-G12D

Cited by 18 publications

References 26 publications

Synergistic anti-tumor activity, reduced pERK, and immuno-stimulatory cytokine profiles with 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in CRC and pancreatic cancer cells independent of G12D mutation

Synergistic anti-tumor activity, reduced pERK, and immuno-stimulatory cytokine profiles with 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in CRC and pancreatic cancer cells independent of G12D mutation

In Silico Prediction of New Inhibitors for Kirsten Rat Sarcoma G12D Cancer Drug Target Using Machine Learning-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulation Approaches

Targeting KRAS in pancreatic cancer

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