KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy

Ryan, Meagan B.; Coker, Oluwadara; Sorokin, Alexey V.; Fella, Katerina A.; Barnes, Haley; Wong, Edmond; Marie, Preeti Kanikarla; Gao, Fengqin; Zhang, Youyan; Zhou, Lian; Kopetz, Scott; Corcoran, Ryan B.

doi:10.1016/j.celrep.2022.110993

Cited by 50 publications

(37 citation statements)

References 43 publications

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“…The inhibition ratio followed a dose-dependent manner in both of these cell lines and realgar induced apoptosis more efficiently in H23 cells. JNK and p38 have been shown to regulate a number of transcription factors, increasing the production of pro-apoptotic proteins while decreasing the expression of anti-apoptotic proteins ( 8 ). Through both transcriptional and post-translational mechanisms, ERK can be anti-apoptotic by upregulating anti-apoptotic proteins and downregulating pro-apoptotic proteins ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

“…In a single-group, phase 2 trial, treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%) ( 7 ). In addition, the response rate of patients with NSCLC to AMG-510 is only 37% ( 8 ). It appears that the identification of effective and safe treatments for NSCLC caused by KRAS mutations remains an ongoing process.…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have shown that the clinical resistance to the KRAS inhibitor AMG-510 in NSCLC is characterized by various pathways, the majority of which converge on the Ras/MAPK pathway ( 23 , 24 ). Inhibition of Ras/MAPK is consequently a big hurdle for enhancing the efficacy in KRAS G12C patients ( 8 ). The process of developing KRAS inhibitors requires not only examination of the mutational status of KRAS, but also regulation of the downstream Ras signaling pathway, which can boost the effectiveness of KRAS inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Realgar‑induced KRAS mutation lung cancer cell death via KRAS/Raf/MAPK mediates ferroptosis

et al. 2022

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KRAS is a biomarker for non-small cell lung cancer-targeted therapy, but there is currently no effective KRAS-targeting medication. Realgar is an impelling anticancer drug, however its significance in KRAS mutant lung cancer is uncertain. According to our findings, the IC 50 of H23 (KRAS mutant) cells is 2.99 times lower than that of H1650 (non-KRAS mutant) cells. Flow cytometry and the Hoechst 33258 staining assay revealed that H1650 cells treated with 4 µg/ml realgar had an apoptotic rate of 8.2%, while H23 cells had a rate of 21.46%. Accordingly, realgar was more sensitive to KRAS mutant cells. Transcriptome sequencing test indicated that there were 481 different expression genes in H23 cells treated with realgar. In H23 cells treated with realgar, mitochondria shrank, inner membrane folding was disturbed, and mitochondrial membrane potential crushed. Realgar boosted intracellular Fe 2+ , reactive oxygen species, malondialdehyde and glutathione levels, which were all reversed by ferroptosis inhibitor Fer-1. Realgar decreased phosphorylated p-Raf, p-ERK1/2 and increased p-p38 and p-JNK, whereas only p-Raf was abolished by Fer-1. Raf inhibitor Sorafenib accelerated the realgar-induced ferroptosis. On H23 cells treated with realgar, the expression of GPX4, SCL7A11 decreased while ACSL4 expression increased; this effect could also be amplified by Sorafenib. In conclusion, the present study indicated that realgar may induce ferroptosis by regulating the Raf, and hence plays a role in anti-KRAS mutant lung cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Realgar‑induced KRAS mutation lung cancer cell death via KRAS/Raf/MAPK mediates ferroptosis

et al. 2022

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“…Distinct signaling networks in lung and CRC might partly explain differences in clinical efficacy. Similar to BRAF V600E inhibition, targeting KRAS G12C and consecutive downregulation of MPAK pathway stimulates EGFR signaling via a negative feedback loop mechanism ( 39 – 41 ). This attenuates the efficacy of Sotorasib or Adagrasib and activates bypass mechanisms.…”

Section: Relevant Clinical Resistance Mechanismsmentioning

confidence: 99%

“…cancer with RAS wild-type tumors: The DEEPER trial (JACCRO CC-13). J Clin Oncol (2021) 39:3501-1. doi: 10.1200/jco.2021 39…”

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confidence: 99%

Current concepts of anti-EGFR targeting in metastatic colorectal cancer

Doleschal¹,

Petzer²,

Rumpold³

2022

Front. Oncol.

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Anti-EGFR targeting is one of the key strategies in the treatment of metastatic colorectal cancer (mCRC). For almost two decades oncologists have struggled to implement EGFR antibodies in the mCRC continuum of care. Both sidedness and RAS mutational status rank high among the predictive factors for the clinical efficacy of EGFR inhibitors. A prospective phase III trial has recently confirmed that anti-EGFR targeting confers an overall survival benefit only in left sided RAS-wildtype tumors when given in first line. It is a matter of discussion if more clinical benefit can be reached by considering putative primary resistance mechanisms (e.g., HER2, BRAF, PIK3CA, etc.) at this early stage of treatment. The value of this procedure in daily routine clinical utility has not yet been clearly delineated. Re-exposure to EGFR antibodies becomes increasingly crucial in the disease journey of mCRC. Yet re- induction or re-challenge strategies have been problematic as they relied on mathematical models that described the timely decay of EGFR antibody resistant clones. The advent of liquid biopsy and the implementation of more accurate next-generation sequencing (NGS) based high throughput methods allows for tracing of EGFR resistant clones in real time. These displays the spatiotemporal heterogeneity of metastatic disease compared to the former standard radiographic assessment and re-biopsy. These techniques may move EGFR inhibition in mCRC into the area of precision medicine in order to apply EGFR antibodies with the increase or decrease of EGFR resistant clones. This review critically discusses established concepts of tackling the EGFR pathway in mCRC and provides insight into the growing field of liquid biopsy guided personalized approaches of EGFR inhibition in mCRC.

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Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies

Caughey,

Strickler

2023

Drugs

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KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy

Cited by 50 publications

References 43 publications

Realgar‑induced KRAS mutation lung cancer cell death via KRAS/Raf/MAPK mediates ferroptosis

Realgar‑induced KRAS mutation lung cancer cell death via KRAS/Raf/MAPK mediates ferroptosis

Current concepts of anti-EGFR targeting in metastatic colorectal cancer

Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies

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