Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance

Ali, Moiez; Kaltenbrun, Erin; Anderson, Grace R.; Stephens, Sarah Jo; Arena, Sabrina; Bardelli, Alberto; Counter, Christopher M.; Wood, Kris C.

doi:10.1038/ncomms15617

Cited by 42 publications

(39 citation statements)

References 50 publications

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“…In contrast, biochemical properties of different KRAS alleles likely contribute to allele selection over a broad spectrum of cancer types (Figure 3E). Other aspects of allele selection are less well characterized (see Outstanding Questions), for example whether KRAS expression level matters, as suggested recently in studies of codon usage [71]. In the end, the “how?” and “why?” of allele choice are less important than the “so what?”.…”

Section: Discussionmentioning

confidence: 99%

KRAS Alleles: The Devil Is in the Detail

2017

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KRAS is the most frequently mutated oncogene in cancer and KRAS mutation is commonly associated with poor prognosis and resistance to therapy. Since the KRAS oncoprotein is, as yet, not directly druggable, efforts to target KRAS mutant cancers focus on identifying vulnerabilities in downstream signaling pathway or in stress-response pathways that are permissive for strong oncogenic signaling. One aspect of KRAS biology that is not well appreciated is the potential biological differences between the many distinct KRAS activating mutations. This review draws upon insights from both clinical and experimental studies to explore similarities and differences among KRAS alleles. Historical and emerging evidence supports the notion that the specific biology related to each allele might be exploitable for allele-specific therapy.

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Section: Discussionmentioning

confidence: 99%

KRAS Alleles: The Devil Is in the Detail

2017

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“…The resistance mechanism to cetuximab shown by many tumor types remains unclear, although KRAS mutation, as well as EGFR mutation and HER2 or MET activation, has been implicated [15][16][17][18][19][20][21][22]. HRAS mutation or upregulated expression of microRNA-100 and microRNA-125b have also been shown to be associated with cetuximab resistance [23,24].…”

Section: Discussionmentioning

confidence: 99%

GC1118, a novel anti-EGFR antibody, has potent KRAS mutation-independent antitumor activity compared with cetuximab in gastric cancer

Park

Jin

Hur³

et al. 2019

Gastric Cancer

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Background EGFR overexpression in gastric cancer (GC) has been reported in about 30% of patients. However, the anti-EGFR antibodies cetuximab and panitumumab have failed to improve overall survival of GC patients in combination with cytotoxic chemotherapy compared with chemotherapy alone. GC1118, a novel anti-EGFR antibody with a distinct binding epitope compared with cetuximab or panitumumab, has not been tested in GC. Methods GC cell lines, SNU-1, SNU-5, SNU-16, SNU-216, SNU-484, SNU-601, SNU-620, SNU-638, SNU-668, SNU-719, AGS, MKN-45, NCI-N87, and KATO-III, were employed to test the effect of cetuximab or GC1118 alone, and combined with the cytotoxic agent cisplatin or 5-fluorouracil (5-FU). Cells were also treat with or without high-affinity ligands EGF 20 ng/ml or HB-EGF 100 ng/ml. Results GC1118 exhibited a more potent growth inhibition effect in the majority of cell lines than cetuximab in MTT assay, regardless of the KRAS mutation status of cell lines. Co-treatment of GC1118 and cisplatin or 5-FU inhibited colony formation and migration to a greater extent, even following EGFR ligand stimulation. Ligand-induced p-AKT and p-ERK upregulation were more potently inhibited by combination treatment with GC1118 and chemotherapeutic agents compared with cetuximab plus chemotherapeutic agents. GC1118 also showed more potent anti-tumor effects compared with cetuximab in a mouse xenograft model. Conclusion Taken together, GC1118 alone or in combination with cytotoxic chemotherapeutic agents exerted more potent anti-tumor effects than cetuximab in GC cells, regardless of KRAS status. These findings support the further clinical development of GC1118 for the treatment of GC.

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“…We had previously demonstrated that ectopic expression of KRAS* generated more protein than KRAS in a variety of cell types (9,39,40). However, the contribution of changing rare codons to common on KRAS mRNA levels in different cells,…”

Section: The Differential Effects Of Codon Usage On Kras Expression Imentioning

confidence: 99%

“…Moreover, such changes had in vivo phenotype, namely altering the proliferation of hematopoetic stem cells or affecting various stages of tumorigenesis (9,39,40). However, the contribution of codon bias to the various steps in KRAS protein production had not been systematically examined.…”

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confidence: 99%

Codon usage regulates human KRAS expression at both transcriptional and translational levels

Dang

Counter

et al. 2018

Journal of Biological Chemistry

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Edited by Karin Musier-Forsyth KRAS and HRAS are highly homologous oncogenic Ras GTPase family members that are mutated in a wide spectrum of human cancers. Despite having high amino acid identity, KRAS and HRAS have very different codon usage biases: the HRAS gene contains many common codons, and KRAS is enriched for rare codons. Rare codons in KRAS suppress its protein expression, which has been shown to affect both normal and cancer biology in mammals. Here, using HRAS or KRAS expression in different human cell lines and in vitro transcription and translation assays, we show that KRAS rare codons inhibit both translation efficiency and transcription and that the contribution of these two processes varies among different cell lines. We observed that codon usage regulates mRNA translation efficiency such that WT KRAS mRNA is poorly translated. On the other hand, common codons increased transcriptional rates by promoting activating histone modifications and recruitment of transcriptional coactivators. Finally, we found that codon usage also influences KRAS protein conformation, likely because of its effect on co-translational protein folding. Together, our results reveal that codon usage has multidimensional effects on protein expression, ranging from effects on transcription to protein folding in human cells.

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Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance

Cited by 42 publications

References 50 publications

KRAS Alleles: The Devil Is in the Detail

KRAS Alleles: The Devil Is in the Detail

GC1118, a novel anti-EGFR antibody, has potent KRAS mutation-independent antitumor activity compared with cetuximab in gastric cancer

Codon usage regulates human KRAS expression at both transcriptional and translational levels

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