Targeting Pathways Downstream of KRAS in Lung Adenocarcinoma
As reviewed above, much has been learned over the past 20 years regarding the pathways that KRAS engages and requires during lung tumorigenesis, and specific inhibitors of these downstream signaling molecules continue to undergo clinical evaluation. Developing effective targeted therapeutic regimens for KRAS-driven lung cancer will probably require the key principle that shaped the formation of combination chemotherapy regimens that have been successful in curing childhood leukemias and certain lymphomas: integration of multiple agents with differing mechanisms of action and nonoverlapping toxicities. It is clear from these regimens, and from the effective therapy of TB and HIV, that probably at least triple-combination drug therapy will be required in order to eradicate the disease and prevent resistance. We conclude this article with theoretical considerations on how to build such regimens in order to target oncogenic KRAS in a rational fashion.
As highlighted above, the key issues facing combination MEK/PI3K inhibitor therapy have been ascribed to the narrow therapeutic window or the failure to induce apoptosis. At the same time, it is clear from numerous studies that inhibiting RAF and PI3K activity in KRAS-driven tumors should be effective at impairing tumorigenesis. The finding that combined inhibition of MEK and IGF1R also accomplishes this goal and has activity in the KP lung cancer model is significant, and suggests that alternative routes to PI3K pathway inhibition may be less toxic and disrupt specific MEK/ERK-regulated feedback loops (Figure 2A). Similarly, inhibition of autocrine cytokine signaling by momelotinib in KRAS-dependent cells is associated with feedback induction of MEK/ERK signaling (Figure 2B), and combined inhibition of both STAT3 and ERK activation through the addition of selumetinib results in impressive synergy in the KP lung cancer GEMM. Furthermore, IGF1R inhibitors such as linsitinib (OSI-906), MEK inhibitors such as selumetinib (AZD6244) or trametinib (GSK1120212) and JAK/TBK1 inhibitors such as momelotinib (CYT387) each have a unique side effect profile and sets of nonoverlapping toxicities. Specifically, dose-limiting toxicities of OSI-906 involve hyperglycemia and MEK inhibitors cause rashes, whereas CYT387 induces cytokine suppression and may predispose individuals to immune compromise. Thus, in contrast to PI3K and MEK inhibitors, which both induce rashes, it is possible that this alternative combination of pathway-targeting agents may achieve potent inhibition of KRAS downstream signaling at doses that could be tolerated together in humans. A particularly rational and appealing strategy would be to evaluate this triple-combination therapy that incorporates suppression of all three major RAS effectors (Figure 1) in preclinical models and, ultimately, in patients.
(Enlarge Image)
Figure 2.
Feedback loops that limit the activity of individual pathway-targeted therapies. (A) MEK inhibition results in feedback activation of IGF1R and downstream PI3K/AKT signaling, with an increase in pAKT levels. Combination therapy with IGF1R inhibitors such as linsitinib (OSI-906) suppresses this feedback and synergizes to inhibit KRAS-driven lung tumorigenesis. (B) TBK1 inhibition leads to induction of MEK/ERK signaling and increased pERK levels through an unclear mechanism. Cotreatment of momelotinib (CYT387) with the MEK inhibitor selumetinib (AZD6244) blocks this compensatory ERK activation and also leads to synergistic tumor regression in aggressive Kras/p53 mutant murine lung cancer.
pAKT: Phosphorylated AKT; pERK: Phosphorylated ERK.
Another important consideration is the heterogeneity of KRAS-driven lung cancers and the fact that specific subsets may be particularly sensitive or resistant to certain therapies. For example, Kras–Lkref-1-mutant murine lung cancer was less sensitive to the docetaxel/selumetinib combination, but might be more sensitive to targeted inhibition of other pathways, particularly in light of its known propensity for inducing cytokine expression. Similarly, the type of oncogenic KRAS mutation could influence the pattern of downstream effector engagement. For example, one study suggested that KRAS and KRAS preferentially induce RAL signaling and are associated with a worse prognosis. However, large numbers of patients and samples will be needed in order to separate the potential confounding of concurrent p53 and LKref-1 tumor-suppressor mutations with oncogenic KRAS mutation type when distinguishing the effectiveness of any particular targeted therapy within these subgroups. Nevertheless, the expansion of clinical genotyping will enable the discovery of subgroups with enhanced responses or resistance to these novel targeted therapeutic approaches that are entering clinical trials.
It is also likely that intratumoral heterogeneity will affect the outcomes of ongoing and future KRAS-targeted therapy trials. For example, two drug regimens that are more effective against a certain subgroup may cause transient tumor regressions, only to be subverted by the outgrowth of clones that cause resistance. However, the identification of patients that respond to a particular drug combination but subsequently become resistant may provide an unbiased way of determining the optimal route to triple-combination therapy by uncovering specific compensatory pathways. Thus, the expansion of novel targeted therapeutic trials directed against downstream KRAS signaling pathways, while hopefully successful, will nevertheless provide a wealth of information and guide the next generation of studies that may bring us closer to the ultimate goal of a cure.
Conclusion: Reflections on Therapy
As reviewed above, much has been learned over the past 20 years regarding the pathways that KRAS engages and requires during lung tumorigenesis, and specific inhibitors of these downstream signaling molecules continue to undergo clinical evaluation. Developing effective targeted therapeutic regimens for KRAS-driven lung cancer will probably require the key principle that shaped the formation of combination chemotherapy regimens that have been successful in curing childhood leukemias and certain lymphomas: integration of multiple agents with differing mechanisms of action and nonoverlapping toxicities. It is clear from these regimens, and from the effective therapy of TB and HIV, that probably at least triple-combination drug therapy will be required in order to eradicate the disease and prevent resistance. We conclude this article with theoretical considerations on how to build such regimens in order to target oncogenic KRAS in a rational fashion.
As highlighted above, the key issues facing combination MEK/PI3K inhibitor therapy have been ascribed to the narrow therapeutic window or the failure to induce apoptosis. At the same time, it is clear from numerous studies that inhibiting RAF and PI3K activity in KRAS-driven tumors should be effective at impairing tumorigenesis. The finding that combined inhibition of MEK and IGF1R also accomplishes this goal and has activity in the KP lung cancer model is significant, and suggests that alternative routes to PI3K pathway inhibition may be less toxic and disrupt specific MEK/ERK-regulated feedback loops (Figure 2A). Similarly, inhibition of autocrine cytokine signaling by momelotinib in KRAS-dependent cells is associated with feedback induction of MEK/ERK signaling (Figure 2B), and combined inhibition of both STAT3 and ERK activation through the addition of selumetinib results in impressive synergy in the KP lung cancer GEMM. Furthermore, IGF1R inhibitors such as linsitinib (OSI-906), MEK inhibitors such as selumetinib (AZD6244) or trametinib (GSK1120212) and JAK/TBK1 inhibitors such as momelotinib (CYT387) each have a unique side effect profile and sets of nonoverlapping toxicities. Specifically, dose-limiting toxicities of OSI-906 involve hyperglycemia and MEK inhibitors cause rashes, whereas CYT387 induces cytokine suppression and may predispose individuals to immune compromise. Thus, in contrast to PI3K and MEK inhibitors, which both induce rashes, it is possible that this alternative combination of pathway-targeting agents may achieve potent inhibition of KRAS downstream signaling at doses that could be tolerated together in humans. A particularly rational and appealing strategy would be to evaluate this triple-combination therapy that incorporates suppression of all three major RAS effectors (Figure 1) in preclinical models and, ultimately, in patients.
(Enlarge Image)
Figure 2.
Feedback loops that limit the activity of individual pathway-targeted therapies. (A) MEK inhibition results in feedback activation of IGF1R and downstream PI3K/AKT signaling, with an increase in pAKT levels. Combination therapy with IGF1R inhibitors such as linsitinib (OSI-906) suppresses this feedback and synergizes to inhibit KRAS-driven lung tumorigenesis. (B) TBK1 inhibition leads to induction of MEK/ERK signaling and increased pERK levels through an unclear mechanism. Cotreatment of momelotinib (CYT387) with the MEK inhibitor selumetinib (AZD6244) blocks this compensatory ERK activation and also leads to synergistic tumor regression in aggressive Kras/p53 mutant murine lung cancer.
pAKT: Phosphorylated AKT; pERK: Phosphorylated ERK.
Another important consideration is the heterogeneity of KRAS-driven lung cancers and the fact that specific subsets may be particularly sensitive or resistant to certain therapies. For example, Kras–Lkref-1-mutant murine lung cancer was less sensitive to the docetaxel/selumetinib combination, but might be more sensitive to targeted inhibition of other pathways, particularly in light of its known propensity for inducing cytokine expression. Similarly, the type of oncogenic KRAS mutation could influence the pattern of downstream effector engagement. For example, one study suggested that KRAS and KRAS preferentially induce RAL signaling and are associated with a worse prognosis. However, large numbers of patients and samples will be needed in order to separate the potential confounding of concurrent p53 and LKref-1 tumor-suppressor mutations with oncogenic KRAS mutation type when distinguishing the effectiveness of any particular targeted therapy within these subgroups. Nevertheless, the expansion of clinical genotyping will enable the discovery of subgroups with enhanced responses or resistance to these novel targeted therapeutic approaches that are entering clinical trials.
It is also likely that intratumoral heterogeneity will affect the outcomes of ongoing and future KRAS-targeted therapy trials. For example, two drug regimens that are more effective against a certain subgroup may cause transient tumor regressions, only to be subverted by the outgrowth of clones that cause resistance. However, the identification of patients that respond to a particular drug combination but subsequently become resistant may provide an unbiased way of determining the optimal route to triple-combination therapy by uncovering specific compensatory pathways. Thus, the expansion of novel targeted therapeutic trials directed against downstream KRAS signaling pathways, while hopefully successful, will nevertheless provide a wealth of information and guide the next generation of studies that may bring us closer to the ultimate goal of a cure.
Source...