Switch Control Kinase Inhibition: Targeting the Kinase Differently to Thwart Drivers of Resistance
Overcoming drug resistance is among the most significant challenges in all of cancer treatment. Novel agents for gastrointestinal stromal tumors (GIST) are being developed to inhibit primary and secondary, drug-resistant mutations in KIT and PDGFRA.
How might switch control kinase inhibition help to improve the treatment of GIST?
Professor of Medicine
“Switch control kinase inhibition has emerged as a promising strategy to address the problem of drug resistance. These novel kinase inhibitors occupy a different binding site in the kinase, the switch pocket, which forces the kinase into an inactive conformation.”
The kinase has a dynamic structure, with active and inactive forms, or conformations, and one of the major problems in KIT- and PDGFRA-mutant GIST relates to these conformational changes. Mutations that favor the active conformation of the kinase can render tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib unable to bind to the target, resulting in resistance to these agents. The established TKIs all bind to the ATP-binding site of the kinase.
Switch control kinase inhibition has emerged as a promising strategy to address the problem of drug resistance. These novel kinase inhibitors occupy a different binding site in the kinase, the switch pocket, which forces the kinase into an inactive conformation. The switch pocket is involved in molecular interactions that permit the kinase to switch from its inactive conformation to its active conformation, somewhat akin to an arm that needs to move to turn the kinase on and off. Ripretinib (DCC-2618) is one such switch control kinase inhibitor that was recently approved by the US Food and Drug Administration based on findings from the INVICTUS trial (NCT03353753), a randomized, double-blind, placebo-controlled trial in 129 patients with GIST who were previously treated with imatinib, sunitinib, and regorafenib. Another strategy to address the problem of resistance owing to mutations that favor the active conformation is the use of a type I TKI (binds to the active conformation). Avapritinib is such an agent that can bind to the active conformation and was approved by the US Food and Drug Administration earlier this year for unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. Since that time, the company developing avapritinib announced plans to discontinue further development of the agent in GIST indications other than PDGFRA exon 18–mutant GIST. Both strategies have shown impressive clinical activity.
Professor of Medicine
“We look forward to learning more about how switch control kinase inhibitors can be used in an optimal way, perhaps including their use in novel combination-based approaches for GIST.”
Switch control kinase inhibition is a novel mechanism that has shown good activity in terms of response rates and progression-free survival. Many questions will be answered in the next few years, and we look forward to learning more about how switch control kinase inhibitors can be used in an optimal way, perhaps including their use in novel combination-based approaches for GIST. For instance, there is the possibility of dual kinase inhibition. We have seen that PLX9486 combined with sunitinib was quite active against highly resistant GIST (NCT02401815), and I would like to think that we are going to develop combination therapies in which a highly active kinase inhibitor such as ripretinib or avapritinib is combined in a novel approach with an immune checkpoint inhibitor or some other agent. We might be able to increase activity with agents that act through any number of mechanisms including metabolic activity, apoptosis, or epigenetic deregulation. Now, resistance has been observed even with these newer agents, and it remains to be seen whether the novel resistance mechanisms are distinct from those of the current treatments. So, another interesting question is whether patients can be cycled back to prior therapies after developing resistance to more recently developed therapies. The use of immunotherapy for GIST, perhaps in combination with targeted therapy, is yet another compelling direction for research. Studies examining interferon alpha in combination with imatinib in patients with metastatic GIST, including a series at our institution, have shown immune cells infiltrating GIST. Our charge is to figure out how to reactivate the immune system and remove the immune escape mechanisms from GIST cells.
“Overcoming drug resistance is among the most significant challenges in all of cancer treatment.”
There are 2 major schools of thought on how cancers such as GIST progress. One is that, even at the time of diagnosis, resistant mutations are present in the tumor, albeit at extremely low frequencies so as to be undetectable. An exon 11–mutant GIST, for example, might harbor very low levels of exon 17 mutants. Over time, selection pressure from targeted therapy would lead to the outgrowth of those tumor cells with exon 17 mutants that were fit to survive treatment. The second theory is that the mutations may not be present initially; however, the genetic instability of the tumor leads to the emergence of resistant clones, a concept similar to the development of antibiotic resistance in bacteria. In either scenario, when mutations in KIT or PDGFRA confer resistance, alternative strategies are needed to overcome it.
Overcoming drug resistance is among the most significant challenges in all of cancer treatment. Kinase inhibitors that bind to the switch pocket use a novel mechanism that is distinct from the ATP-competitive nature of inhibition with imatinib, sunitinib, and regorafenib. At least in vitro, ripretinib demonstrates a broad range of activity against the secondary mutations, particularly KIT exon 17 mutants, which represent one of the major clinical challenges in this disease.
There are also clues to an immune response to GIST, and harnessing the power of the immune system to fight GIST may be another method to complement our current strategies. We see that there are T cells and tumor-associated macrophages, which many consider to be immunosuppressive, in the GIST microenvironment. One strategy that is currently being explored is the elimination of these putatively immunosuppressive macrophages. Also, studies in mice show that a combination of imatinib plus immune checkpoint inhibitors is more efficacious than imatinib alone. Studies have also reported greater than expected immune infiltration to GIST with interferon and imatinib. Our own small study of nivolumab, or nivolumab plus ipilimumab, demonstrated a clinical benefit in approximately one-third of patients who were refractory to all other agents. There were 4 patients on therapy for more than 2 years with immune checkpoint inhibitors; it is uncommon to find an agent that lasts that long in the advanced/refractory setting. There is certainly some activity of immune checkpoint inhibitors in GIST, and finding the right combination of therapies, as well as which patients are most likely to receive benefit, will be the subject of research going forward.
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ClinicalTrials.gov. A study of DCC-2618 vs sunitinib in advanced GIST patients after treatment with imatinib (intrigue). Accessed May 6, 2020. https://clinicaltrials.gov/ct2/show/NCT03673501
ClinicalTrials.gov. Phase 3 study of DCC-2618 vs placebo in advanced GIST patients who have been treated with prior anticancer therapies (invictus). Accessed May 20, 2020. https://clinicaltrials.gov/ct2/show/NCT03353753
ClinicalTrials.gov. PLX9486 as a single agent and in combination with PLX3397 or PLX9486 with sunitinib in patients with advanced solid tumors. Accessed May 6, 2020. https://clinicaltrials.gov/ct2/show/NCT02401815
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