The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity

Canon, Jude; Rex, Karen; Saiki, Anne Y.; Mohr, Christopher; Cooke, Keegan S.; Bagal, Dhanashri; Gaida, Kevin; Holt, Tyler; Knutson, Charles G.; Koppada, Neelima; Lanman, Brian A.; Werner, Jonathan; Rapaport, Aaron S.; Miguel, Tisha San; Ortiz, Roberto; Osgood, Tao; Sun, J. R.; Zhu, Xiaochun; McCarter, John D.; Volak, Laurie P.; Houk, Brett E.; Fakih, Marwan; O’Neil, Bert H.; Price, Timothy; Falchook, Gerald S.; Desai, Jayesh; Kuo, James; Govindan, Ramaswamy; Hong, David S.; Ouyang, Wenjun; Henary, H.; Arvedson, Tara; Cee, Victor J.; Lipford, J. Russell

doi:10.1038/s41586-019-1694-1

Cited by 1,446 publications

(1,390 citation statements)

References 32 publications

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“…For mutant RAS-GTP, the predicted dose response for KRAS G12C inhibition showed increasing levels of synergy for increasing levels of coincident EGFR inhibition (Figure 7B). This is consistent with previous empirical results (12,13,23,24) and with our original KRAS G12C modeling (21). Additionally, the model suggests that there will also be considerable levels of synergy for WT RAS-GTP ( Figure 7C).…”

Section: Simulations Suggest Combined Treatment Of Kras G12c Inhibitosupporting

confidence: 92%

“…To investigate whether these findings would generalize to other CRC cell lines, we obtained two KRAS G12C CRC cell lines: SW837 (heterozygous KRAS G12C mutant) and SW1463 (homozygous KRAS G12C mutant) (12). We observed SW837 cells to be sensitive to cetuximab (IC50 of 0.793 µM) but not the SW1463 cells ( Figure 1C).…”

Section: Heterozygous Mutant Kras G12c Crc Cells Are Sensitive To Egfmentioning

confidence: 84%

“…KRAS G12C covalent inhibitors have recently been developed that appear capable of specifically targeting and inhibiting KRAS G12C (10)(11)(12)(13)23). Early reports from clinical trials are promising (12,13). We tested the ability of KRAS G12C inhibitor AMG-510 (12) to specifically target KRAS G12C in the CRC cells we have been studying.…”

Section: Kras G12c Covalent Inhibition By Amg-510 Results In Reducedmentioning

confidence: 99%

“…Previously, it has been empirically shown that co-targeting EGFR along with a G12C inhibitor can result in increased inhibition of the KRAS G12C mutant in lung cancer and pancreatic cancer cell lines (12,13,(23)(24)(25)(26). We desired to test this combination in our colorectal cancer cells.…”

Section: Egfr Inhibitorsmentioning

confidence: 99%

“…A major advance in RAS biology has been the development of small molecules that can covalently interact specifically with this Cysteine residue that is unique to the G12C mutant (10,11), thus conferring the longsought ability to pharmaceutically target mutant, but not wild-type, RAS (3). Some of these agents are now in clinical trials, and early reports are promising (12,13). However, there is also the expectation that KRAS G12C inhibitors will need to be used in combination regimens.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of both mutant and wild-type RAS-GTP in KRAS G12C colorectal cancer through cotreatment with G12C and EGFR inhibitors

McFall

Trogdon

Sisk-Hackworth

et al. 2019

Preprint

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Multiple KRAS G12C inhibitors are in development, and the identification of effective combination treatment regimens should maximize the benefit these agents have on cancer patients. Here, we find that KRAS G12C heterozygous mutated colorectal cancer cells are sensitive to targeting with EGFR therapeutic antibodies. We find that KRAS G12C is partially impaired in binding to tumor suppressor NF1 and also to RAF, and our computational simulations reveal how these deficiencies result in partial sensitivity to EGFR inhibition. For the combination of EGFR and G12C inhibitors we observe synergy and reductions in active forms of both wild-type and mutant RAS. Our simulations reveal the synergy involves both wild-type and mutant RAS. Overall, our work suggests that the addition of an EGFR inhibitor to a KRAS G12C inhibitor regimen should be further evaluated as a strategy for KRAS G12C colorectal cancer patients.

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Section: Simulations Suggest Combined Treatment Of Kras G12c Inhibitosupporting

confidence: 92%

Section: Heterozygous Mutant Kras G12c Crc Cells Are Sensitive To Egfmentioning

confidence: 84%

Section: Kras G12c Covalent Inhibition By Amg-510 Results In Reducedmentioning

confidence: 99%

Section: Egfr Inhibitorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of both mutant and wild-type RAS-GTP in KRAS G12C colorectal cancer through cotreatment with G12C and EGFR inhibitors

McFall

Trogdon

Sisk-Hackworth

et al. 2019

Preprint

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KRAS Allelic Variants in Biliary Tract Cancers

Moffat,

Hu,

Meric-Bernstam

et al. 2024

JAMA Netw Open

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ImportanceBiliary tract cancers (BTCs) contain several actionable molecular alterations, including FGFR2, IDH1, ERBB2 (formerly HER2), and KRAS. KRAS allelic variants are found in 20% to 30% of BTCs, and multiple KRAS inhibitors are currently under clinical investigation.ObjectivesTo describe the genomic landscape, co–sequence variations, immunophenotype, genomic ancestry, and survival outcomes of KRAS-mutated BTCs and to calculate the median overall survival (mOS) for the most common allelic variants.Design, Setting, and ParticipantsThis retrospective, multicenter, pooled cohort study obtained clinical and next-generation sequencing data from multiple databases between January 1, 2017, and December 31, 2022. These databases included Princess Margaret Cancer Centre, MD Anderson Cancer Center, Foundation Medicine, American Association for Cancer Research Project GENIE, and cBioPortal for Cancer Genomics. The cohort comprised patients with BTCs who underwent genomic testing.Main Outcome and MeasureThe main outcome was mOS, defined as date of diagnosis to date of death, which was measured in months.ResultsA total of 7457 patients (n = 3773 males [50.6%]; mean [SD] age, 63 [5] years) with BTCs and genomic testing were included. Of these patients, 5813 had clinical outcome data available, in whom 1000 KRAS-mutated BTCs were identified. KRAS allelic variants were highly prevalent in perihilar cholangiocarcinoma (28.6%) and extrahepatic cholangiocarcinoma (36.1%). Thirty-six KRAS allelic variants were identified, and the prevalence rates in descending order were G12D (41%), G12V (23%), and Q61H (8%). The variant G12D had the highest mOS of 25.1 (95% CI, 22.0-33.0) months compared with 22.8 (95% CI, 19.6-31.4) months for Q61H and 17.8 (95% CI, 16.3-23.1) months for G12V variants. The majority of KRAS-mutated BTCs (98.9%) were not microsatellite instability–high and had low tumor mutational burden (ranging from a median [IQR] of 1.2 (1.2-2.5) to a mean [SD] of 3.3 [1.3]). Immune profiling through RNA sequencing of KRAS and NRAS–mutated samples showed a pattern toward a more immune-inflamed microenvironment with higher M1 macrophage activation (0.16 vs 0.12; P = .047) and interferon-γ expression compared with wild-type tumors. The G12D variant remained the most common KRAS allelic variant in all patient ancestries. Patients with admixed American ancestry had the highest proportion of G12D variant (45.0%).Conclusions and RelevanceThis cohort study found that KRAS allelic variants were relatively common and may be potentially actionable genomic alterations in patients with BTCs, especially perihilar cholangiocarcinoma and extrahepatic cholangiocarcinoma. The findings add to the growing data on genomic and immune landscapes of KRAS allelic variants in BTCs and are potentially of value to the planning of specific therapies for this heterogeneous patient group.

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Fragment‐Based Lead Discovery

Hubbard

2021

Burger's Medicinal Chemistry and Drug Discovery

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Fragment‐based discovery is an effective approach to finding hit compounds that bind to a target. Fragments can be found that bind to most sites on most proteins, providing a rich source of chemical ideas for the medicinal chemist to develop into hits and leads. There are two distinctive activities in fragment‐based discovery: (i) finding fragments that bind and (ii) evolving the fragments to hit compounds which can then be progressed using conventional (structure‐guided) optimization. A wide variety of methods have been developed for screening, many based on biophysical approaches to identify and then characterize the binding of the relatively low affinity (but efficient) compounds – a separate section summarizes the key features of the methods. Perhaps the most difficult aspect of fragment‐based discovery is deciding which fragments to evolve – another section describes some recent projects to highlight the key strategies that are used. The article concludes with some summary statements on the main features and advantages of the approach and a discussion about future directions.

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The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity

Cited by 1,446 publications

References 32 publications

Inhibition of both mutant and wild-type RAS-GTP in KRAS G12C colorectal cancer through cotreatment with G12C and EGFR inhibitors

Inhibition of both mutant and wild-type RAS-GTP in KRAS G12C colorectal cancer through cotreatment with G12C and EGFR inhibitors

KRAS Allelic Variants in Biliary Tract Cancers

Fragment‐Based Lead Discovery

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