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?

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?

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?

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?

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?