Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges

Tang, Daolin; Kroemer, Guido; Kang, Rui

doi:10.1186/s12943-021-01422-7

Cited by 51 publications

(48 citation statements)

References 214 publications

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“…As SHP2 and SOS1 are the common nodes of RTK signals SHP2 inhibitors or SOS1 inhibitors may either enhance the activity of KRAS G12C inhibitors or reverse adaptive resistance. This hypothesis has been confirmed in pre-clinical models [ 51 ].…”

Section: Secondary Resistance To Kras G12 Inhibitionmentioning

confidence: 59%

“…The insulin-like growth factor receptor (IGF-1R) pathways mediates PI3K activation in a SHP2-independent manner in vitro, and leads to increased MAPK signaling via FGFR [ 44 ]. The mechanism of PI3K pathway mediated resistance to KRAS G12C inhibitors may depend on the tumor type and the degree of cell de-differentiation [ 51 ].…”

Section: Secondary Resistance To Kras G12 Inhibitionmentioning

confidence: 99%

“…KRAS G12C therapy resistance could impair antitumor immunity [ 9 , 51 ]. In vitro analysis shows that an impaired host immune system may confer resistance independent of MAPK reactivation or proliferative signaling [ 19 ].…”

Section: Secondary Resistance To Kras G12 Inhibitionmentioning

confidence: 99%

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Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance

Reita

Pabst

Pencreach

et al. 2022

Cancers

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KRAS is the most frequently mutated oncogene in non-small cell lung cancers (NSCLC), with a frequency of around 30%, and encoding a GTPAse that cycles between active form (GTP-bound) to inactive form (GDP-bound). The KRAS mutations favor the active form with inhibition of GTPAse activity. KRAS mutations are often with poor response of EGFR targeted therapies. KRAS mutations are good predictive factor for immunotherapy. The lack of success with direct targeting of KRAS proteins, downstream inhibition of KRAS effector pathways, and other strategies contributed to a focus on developing mutation-specific KRAS inhibitors. KRAS p.G12C mutation is one of the most frequent KRAS mutation in NSCLC, especially in current and former smokers (over 40%), which occurs among approximately 12–14% of NSCLC tumors. The mutated cysteine resides next to a pocket (P2) of the switch II region, and P2 is present only in the inactive GDP-bound KRAS. Small molecules such as sotorasib are now the first targeted drugs for KRAS G12C mutation, preventing conversion of the mutant protein to GTP-bound active state. Little is known about primary or acquired resistance. Acquired resistance does occur and may be due to genetic alterations in the nucleotide exchange function or adaptative mechanisms in either downstream pathways or in newly expressed KRAS G12C mutation.

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Section: Secondary Resistance To Kras G12 Inhibitionmentioning

confidence: 59%

Section: Secondary Resistance To Kras G12 Inhibitionmentioning

confidence: 99%

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Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance

Reita

Pabst

Pencreach

et al. 2022

Cancers

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“…In general, KRAS gene mutation at different prevalence rates is associated with a series of highly fatal cancers. The top 5 human cancers among these KRAS somatic mutations are pancreas (57%), large intestine (35%), biliary tract (28%), small intestine (17%) and lung (16%) [ 21 ]. Apparently, the mutation sites and frequencies of KRAS gene were varied from diverse human tumor types.…”

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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“…The RAS family of cell membrane-anchored GTPases (HRAS, NRAS and KRAS) activates downstream proteins (e.g., PI3K and BRAF kinases) when bound to guanosine triphosphate (GTP). Constitutively activated (mutated) GTP-bound RAS isoforms stimulate downstream effector pathways, even in the absence of extracellular stimuli ( Figure 2 ) [ 45 , 46 ]. The utility of RAS mutations as a diagnostic tool is rather low [ 44 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Inhibitor-Based Therapies for Thyroid Cancer—An Update

Ratajczak

Gawel

Godlewska

2021

IJMS

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Thyroid cancers (TCs) are the most common tumors of the endocrine system and a constant rise in the number of TC cases has been observed for the past few decades. TCs are one of the most frequent tumors in younger adults, especially in women, therefore early diagnosis and effective therapy are especially important. Ultrasonography examination followed by fine needle biopsy have become the gold standard for diagnosis of TCs, as these strategies allow for early-stage detection and aid accurate qualification for further procedures, including surgical treatment. Despite all the advancements in detection and treatment of TCs, constant mortality levels are still observed. Therefore, a novel generation line of targeted treatment strategies is being developed, including personalized therapies with kinase inhibitors. Recent molecular studies on TCs demonstrate that kinase inhibitor-based therapies might be considered as the most promising. In the past decade, new kinase inhibitors with different mechanisms of action have been reported and approved for clinical trials. This review presents an up-to-date picture of new approaches and challenges of inhibitor-based therapies in treatment of TCs, focusing on the latest findings reported over the past two years.

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Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges

Cited by 51 publications

References 214 publications

Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance

Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance

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

Novel Inhibitor-Based Therapies for Thyroid Cancer—An Update

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