KRAS mutation: from undruggable to druggable in cancer

Huang, Lamei; Guo, Zhixing; Wang, Fang; Fu, Liwu

doi:10.1038/s41392-021-00780-4

Cited by 411 publications

(384 citation statements)

References 233 publications

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“…This mutation is associated with low to moderate sensitivity to the tyrosine kinase inhibitors imatinib, sunitinib, dasatinib, and nilotinib in vitro [ 37 , 38 ]. The other pathogenic SNVs, particularly ERBB2 p.(Val773Met) and KRAS p.(Gln61Leu), are still undruggable molecular targets in solid tumours, despite promising data from preclinical models, clinical trials and case reports [ 39 , 40 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas

Szpechcinski¹,

Szołkowska²,

Winiarski³

et al. 2022

Cancers

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A better understanding of the molecular pathogenesis of thymic epithelial tumours (TETs) could revolutionise their treatment. We evaluated thymomas and thymic carcinomas by next-generation sequencing (NGS) of somatic or germline single nucleotide variants (SNVs) in genes commonly mutated in solid tumours. In total, 19 thymomas and 34 thymic carcinomas were analysed for nonsynonymous SNVs in 15 genes by targeted NGS (reference genome: hg19/GRCh37). Ten SNVs in TP53 (G154V, R158P, L194H, R267fs, R273C, R306 *, Q317 *), ERBB2 (V773M), KIT (L576P), and KRAS (Q61L) considered somatic and pathogenic/likely pathogenic were detected in 10 of 34 (29.4%) thymic carcinomas. No somatic SNVs confirmed as pathogenic/likely pathogenic were found in thymomas. Rare SNVs of uncertain or unknown functional and clinical significance, to our knowledge not reported previously in TETs, were found in ERBB2 (S703R), KIT (I690V), and FOXL2 (P157S) in 3 of 19 (16%) thymomas. The most frequent germline SNVs were TP53 P72R (94% TETs), ERBB2 I655V (40% TETs), and KIT M541L (9% TETs). No significant difference in median disease-free survival (DFS) was found between thymic carcinoma patients with and without pathogenic SNVs (p = 0.190); however, a trend toward a longer DFS was observed in the latter (16.0 vs. 30.0 months, respectively). In summary, NGS analysis of TETs revealed several SNVs in genes related to the p53, AKT, MAPK, and K-Ras signalling pathways. Thymic carcinomas showed greater genetic dysregulation than thymomas. The germline and rare SNVs of uncertain clinical significance reported in this study add to the number of known genetic alterations in TETs, thus extending our molecular understanding of these neoplasms. Druggable KIT alterations in thymic carcinomas have potential as therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas

Szpechcinski¹,

Szołkowska²,

Winiarski³

et al. 2022

Cancers

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“…Finally, KRAS is the most frequently mutated oncoprotein, occurring in over 25% of all cancer patients. Due to its smooth and shallow surface, it is considered largely undruggable by standard small molecules, and its structure is evasive due to its conformational disorder as a transcription factor protein [Huang et al, 2021].…”

Section: Resultsmentioning

confidence: 99%

Design of Peptide-Based Protein Degraders via Contrastive Deep Learning

Palepu

Ponnapati

Bhat

et al. 2022

Preprint

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Therapeutic modalities targeting pathogenic proteins are the gold standard of treatment for multiple disease indications. Unfortunately, a significant portion of these proteins are considered "undruggable" by standard small molecule-based approaches, largely due to their disordered nature and instability. Designing functional peptides to undruggable targets, either as standalone binders or fusions to effector domains, thus presents a unique opportunity for therapeutic intervention. In this work, we adapt recent models for contrastive language-image pre-training (CLIP) to devise a unified, sequence-based framework to design target-specific peptides. Furthermore, by leveraging known experimental binding proteins as scaffolds, we create a streamlined inference pipeline, termed Cut&CLIP, that efficiently selects peptides for downstream screening. Finally, we experimentally fuse candidate peptides to E3 ubiquitin ligase domains and demonstrate robust intracellular degradation of pathogenic protein targets in human cells, motivating further development of our technology for future clinical translation.

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“…Apparently, the mutation sites and frequencies of KRAS gene were varied from diverse human tumor types. For example, three amino acid residues with missense mutations including G12(codon 12), G13(codon 13), and Q61(codon 61) are the most common mutation sites with distinct mutation frequencies in different cancers [ 22 ]. Among these mutations, point mutations in KRAS codon 12 are probably the most common event, which accounts for approximately 80% of KRAS mutation [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

KRAS acting through ERK signaling stabilizes PD-L1 via inhibiting autophagy pathway in intrahepatic cholangiocarcinoma

Gao

Chen

et al. 2022

Cancer Cell Int

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Background While the correlation between PD-L1 expression and KRAS mutation has been previously reported in other solid tumors such as non-small cell lung cancer (NSCLC), whether PD-L1 can be modulated by ERK signaling downstream of KRAS in intrahepatic cholangiocarcinoma (iCCA) and the underlying molecular regulatory mechanism remain unclear. Methods The expression of ERK, p-ERK, PD-L1 and autophagy markers following KRAS knockdown or Ras/Raf/MEK/ERK signaling inhibitors treatment was examined in two human iCCA cell lines (HuCCT1 and RBE) using western blotting and immunofluorescence. Both pharmacological autophagy inhibitors and short-interfering RNA against ATG7 were applied to inhibit autophagy. The apoptosis rates of iCCA cell lines were detected by flow cytometry and CCK-8 after co-culturing with CD3/CD28-activated human CD8+ T lymphocytes. Immunohistochemistry was applied to detect the correlation of ERK, p-ERK and PD-L1 in 92 iCCA tissues. Results The present study demonstrated that the PD-L1 expression level was distinctly reduced in KRAS-mutated iCCA cell lines when ERK signaling was inhibited and ERK phosphorylation levels were lowered. The positive association between p-ERK and PD-L1 was also verified in 92 iCCA tissue samples. Moreover, ERK inhibition induced autophagy activation. Both inhibiting autophagy via autophagy inhibitors and genetically silencing the ATG7 expression partially reversed the reduced PD-L1 expression caused by ERK inhibition. In addition, ERK-mediated down-regulation of PD-L1 via autophagy pathways induced the apoptosis of iCCA cells when co-cultured with CD3/CD28-activated human CD8+ T lymphocytes in vitro. Conclusions Our results suggest that ERK signaling inhibition contributes to the reduction of PD-L1 expression through the autophagy pathway in iCCA. As a supplement to anti-PD-1/PD-L1 immunotherapy, ERK-targeted therapy may serve as a potentially novel treatment strategy for human KRAS-mutated iCCA.

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KRAS mutation: from undruggable to druggable in cancer

Cited by 411 publications

References 233 publications

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas

Design of Peptide-Based Protein Degraders via Contrastive Deep Learning

KRAS acting through ERK signaling stabilizes PD-L1 via inhibiting autophagy pathway in intrahepatic cholangiocarcinoma

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