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?
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Anonymous User4yrCombining 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 downstream and combining it with KRAS may help overcome Potential resistance to KRAS inhibitors.
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Alireza Mirmiran4yrI agree: potentially use combinations of KRAS-G12C inhibitors would be with checkpoint inhibitors, cytotoxic chemotherapy, and radiotherapy.
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Jaimelynn Gallozzi4yrIt would be of interes t to combine agentd w chemo, combine w prednisone, radiation and also follow how many patients need surgical intervention as there treatment after receiving this therapy
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Russell Simkins, Pharmacy Manager4yrI believe the mTOR and IGF1R combination with the G12C inhibitors would have the best potential for therapy because they inhibit the principal signaling pathways required for the survival of KRAS-mutant cells and produces marked tumor regression in three different KRAS-driven lung cancer mouse models. However, I would like to see the MEK combination continued to be investigated.
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Mayer Gorbaty4yrIt would be of interest to combine these agents with standard chemotherapy; with immunotherapy; with radiation; combinations of all of the above.