KRAS Oncogene Connect
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Leveraging the therapeutic potential of KRAS-G12C inhibitors

Previous strategies to indirectly target KRAS have failed in clinical trials; however, newer drugs are able to directly inhibit KRAS-G12C by selectively forming a covalent bond with cysteine 12 within the switch-II pocket of KRAS-G12C protein, thus forcing KRAS in the inactive state to cease cell proliferation. Of particular interest is that the specificity of this mechanism of action likely reduces associated toxicity.



Clinical trials focusing on combination treatments involving KRAS-G12C inhibitors are at the fore. The rationale for such trials is partly based on outcomes of in vitro or mouse trials involving the addition of agents such as mTOR and IGF1R inhibitors to boost the activity of KRAS-G12C inhibitors against KRAS-G12C mutant lung cancer cells. Combination with MEK inhibitors is another strategy, which is notable because MEK inhibitors are considered too toxic for use on their own.



Combining KRAS-G12C inhibitors with other agents is hypothesized to attain more durable and significant responses. What combinations do you think may be of potential clinical utility and why?


  • 4yr
    Combining KRAS inhibitors with SHP2 inhibitors may help in enhancing the effect or RTK inhibitors. Using MTORs can be complimentary as another pathway is inhibited simultaneously. RAF pathway is further Show More
  • 4yr
    I agree: potentially use combinations of KRAS-G12C inhibitors would be with checkpoint inhibitors, cytotoxic chemotherapy, and radiotherapy.

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4yr
Inhibition of cytoplasmic EZH2 induces antitumor activity through stabilization of the DLC1 tumor suppressor protein - PubMed

Inhibition of cytoplasmic EZH2 induces antitumor activity through stabilization of the DLC1 tumor suppressor protein - PubMed

Source : https://pubmed.ncbi.nlm.nih.gov/34862367/

mRNA expression of the DLC1 tumor suppressor gene is downregulated in many lung cancers and their derived cell lines, with DLC1 protein levels being low or absent. Although the role...


Conclusion: These rational drug combinations induce potent tumor growth inhibition, with markers of apoptosis and senescence, that is highly dependent on DLC1 protein.

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4yr
Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Inhibitor - PubMed

Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Inhibitor - PubMed

Source : https://pubmed.ncbi.nlm.nih.gov/34889605/

KRAS G12D , the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRAS G12C , selective inhibition of KRAS...


Conclusion/Relevance: Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.

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4yr
Resistance looms for KRAS G12C inhibitors and rational tackling strategies

Resistance looms for KRAS G12C inhibitors and rational tackling strategies

Source : https://www.sciencedirect.com/science/article/abs/pii/S0163725821002527?via=ihub

KRAS mutations are one of the most frequent activating alterations in carcinoma. Recent efforts have witnessed a revolutionary strategy for KRAS G12C ...


Conclusion/Relevance: Herein, we first briefly discuss the recent resistance looms for KRAS G12C inhibitors, focusing on their clinical trials. We then comprehensively interrogate and underscore our current understanding of resistance mechanisms and the necessity of incorporating genomic analyses into the clinical investigation to further...

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4yr
Genomic profiles and their associations with TMB, PD-L1 expression, and immune cell infiltration landscapes in synchronous multiple primary lung cancers - PubMed

Genomic profiles and their associations with TMB, PD-L1 expression, and immune cell infiltration landscapes in synchronous multiple primary lung cancers - PubMed

Source : https://pubmed.ncbi.nlm.nih.gov/34887263/

MPLCs are driven by different molecular events and often exhibit low TMB, low PD-L1, and a heterogeneous immune infiltration landscape. Specific genomic profiles are associated with TMB and the tumor...


Conclusion: MPLCs are driven by different molecular events and often exhibit low TMB, low PD-L1, and a heterogeneous immune infiltration landscape. Specific genomic profiles are associated with TMB and the tumor immune microenvironmental landscape in MPLCs. Our findings can help to guide MPLCs diagnoses and to identify patient populations that...