MAP2K4: New kid on the MAP Kinase block
, by Robin A Jansen and Rene Bernards
Robin A Jansen is a post-doctoral fellow at the lab of Rene Bernards at the Netherlands Cancer Institute in Amsterdam. Her research focuses on finding effective drug combinations in the MAP kinase pathway.
Rene Bernards is a senior staff scientist at the Netherlands Cancer Institute. His laboratory focuses on finding highly effective drug combinations for cancer.
The concept of targeted therapy in the fight against cancer was first proposed by German Nobel laureate Paul Ehrlich in the 1890s, long before the identification of the first cancer-causing oncogenes. Ehrlich described this concept as ‘magic bullets’ that would be completely specific for the target and therefore safe without any additional toxicity to the body 1. However, for decades, due to lack of knowledge regarding the biological hallmarks of cancer, anticancer drugs were limited to cytotoxic chemotherapeutic agents that would affect not only the tumor cells but also healthy tissue, causing extensive toxicity. This landscape of anticancer therapy would drastically change with the discovery of oncogenes in the 1980s and the subsequent elucidation of the cancer-causing mutations in these genes, which has enabled the development of targeted anticancer drugs as ‘magic bullets’ for use in the fight against cancer 2.
Despite being identified as one of the first and most frequent oncogenic drivers over four decades ago, it was not until very recently that the first RAS inhibitor, a mutant selective KRASG12C inhibitor, was approved by the FDA for the treatment of KRASG12C mutant non-small cell lung cancer (NSCLC) patients 3. RAS was formerly considered to be ‘undruggable’, but a broad arsenal of targeted drugs that inhibit RAS or specific RAS mutants quickly followed the initial discovery of the KRASG12C-specific inhibitors 4,5. Unfortunately, despite initial clinical responses in KRASG12C mutant NSCLC patients, monotherapeutic KRASG12C inhibition did not achieve meaningful overall survival (OS) benefit, as resistance to single-agent therapies often inevitably develops in advanced cancers 6. Moreover, while NSCLC patients experienced significant progression-free survival (PFS) benefit by treatment with the mutant-selective KRASG12C inhibitor sotorasib, colorectal cancer (CRC) patients harboring the same genetic mutation did not show meaningful improvement. Therefore, there is a need to decipher the mechanisms of resistance to these RAS inhibitors, as deep insights into the molecular mechanisms underlying resistance to RAS-targeted therapy can ultimately help improve clinical responses.
RAS inhibitors suffer from the same issue seen with other inhibitors that target the downstream mitogen-activated protein kinase (MAPK) pathway, namely that their effectiveness as single-agents in KRAS-driven cancers is limited by feedback mechanisms that re-activate the MAPK pathway in the presence of drug. It is well established that feedback activation of upstream receptor tyrosine kinases (RTKs) is a frequent feedback mechanism to RAS pathway inhibition and disabling this feedback activation by concomitant inhibition can be highly effective to enhance the effect of MAPK inhibitors. This was first discovered after the clinical observation that BRAF inhibition by vemurafenib did not show similar meaningful clinical responses in CRCs compared to melanomas harboring the same BRAF mutation7. Mechanistically, it turned out that the feedback activation of EGFR upon inhibition of mutant BRAF precludes the response to BRAF inhibitor monotherapy in this disease and the combination of BRAF and EGFR inhibitors is now approved as a therapeutic strategy for the treatment of BRAF-mutant colon cancer8,9. In KRAS-mutant cancers, inhibition of upstream RTKs by using pan-HER tyrosine kinase inhibitors has also been shown to be synergistic with MEK inhibition 10. Based on these encouraging pre-clinical results, several clinical trials were conducted combining pan-HER and MEK inhibitors in KRAS-mutant cancers 11-13. Unfortunately, clinical development has been discontinued due to the frequent treatment-related toxicities of these combinations. Clinical trial failure caused by toxicity is common in oncology, especially in combination studies as a result of overlapping toxicity profiles of the individual targeted agents, also referred to as ‘supra-additive toxicities’, and unexpected toxicities specific for the drug combination 14. Therefore, it is important to identify drug combinations that are not only highly effective but also simultaneously minimize toxicity in cancer patients.
While most KRAS-mutant cancers are refractory to inhibitors of the MAPK pathway, Xue et al showed that cancer cells that lack MAP2K4 respond to MEK or ERK inhibitor monotherapy, making MAP2K4 and interesting target for combination studies in the MAPK pathway 15. Mechanistically, RAS pathway inhibition increases MAP2K4-JNK-JUN pathway signaling through inhibition of DUSP4, which in turn activates several RTKs, especially ERBB2 and ERBB3, that subsequently reactivate the RAS pathway in the presence of drug 15. Consequently, genetic loss of MAP2K4 confers sensitivity to RAS pathway inhibitors in multiple KRAS-mutant cancer models 15,16. As selective MAP2K4 inhibitors have recently been developed, this provides a potentially novel combination treatment strategy for KRAS-mutant cancers 17,18. Therefore, MAP2K4 is a new player in the KRAS game that could pave the way for yet unexplored therapeutic strategies in the treatment of KRAS-driven cancers. Indeed, we found that the novel MAP2K4 inhibitor HRX-0233 is highly synergistic with various RAS pathway inhibitors in KRAS-mutant NSCLC and CRC cancer models 16. Moreover, the combination of the novel MAP2K4 inhibition and KRASG12C-specific inhibitor sotorasib, is well-tolerated and resulted in durable tumor shrinkage in mouse xenografts of human lung cancer cells, suggesting a novel therapeutic strategy for KRAS-driven cancers, which currently lack effective treatment options.
A key question is whether this novel drug combination will be less toxic in cancer patients. Importantly, while MAP2K4 also blocks the feedback activation of HER RTKs upon RAS pathway inhibition, this novel combination is fundamentally different in that MAP2K4 inhibition only prevents the increased expression and activity of RTKs that occurs upon MAPK inhibition, whereas the pan-HER inhibitors also block basal levels of the RTK activity. As such, combining RAS pathway inhibitors with a MAP2K4 inhibitor rather than a pan-HER inhibitor may have a more favorable toxicity profile. Additionally, combining small molecule MAP2K4 inhibitors with mutant-selective inhibitors like the KRASG12C-mutant-selective inhibitor sotorasib provides an opportunity to achieve an even better therapeutic window that maximizes efficacy and minimizes adverse effects. Moreover, as overlapping toxicity profiles of individual drugs have proven to be a major hurdle, a potential advantage of the use of MAP2K4 inhibitors is the absence of treatment-related adverse events observed in a recent phase I clinical trial in healthy volunteers evaluating increasing doses of another small molecule MAP2K4 inhibitor, HRX-0215 19. This favorable toxicity profile potentially makes small molecule MAP2K4 inhibitors an ideal combinational strategy partner.
Notably, this is the first study evaluating the use of a MAP2K4 inhibitor in a clinical setting. Nevertheless, there is growing interest in MAP2K4 as a promising drug target, as increasing evidence is demonstrating the significance of MAP2K4 in cancer development, progression and metastasis, as well as in acute and chronic liver diseases18,20 For instance, another novel MAP2K4 inhibitor, PLX8725, demonstrated activity in MAP2K4-gene-amplified uterine leiomyosarcomas (uLMS) patient-derived xenograft (PDX) models, opening up more opportunities to test the utility of pharmacological inhibition of MAP2K4 for anti-cancer therapy21.
Currently, the old paradigm still embraced by pharmaceutical companies requires targeted anticancer drugs to demonstrate single-agent activity before evaluating combination strategies. Thus, targeted cancer drugs are initially developed as single-agent and only tested in combination after seeing initial good responses as a monotherapy. It is important to consider abandoning this old paradigm as BRAF inhibition monotherapy in colon cancer is ineffective, but did show activity in combination. Analogously, while pharmacological inhibition of MAP2K4 does not appear to have a major effect on KRAS-driven cancer cells as a monotherapy, we showed that MAP2K4 inhibition may become powerful when used in combination for the treatment of KRAS-mutant cancers. It will be interesting to see whether this combination delivers clinical benefit. There are always uncertainties in translating pre-clinical concepts to human testing. As the famous baseball coach Yogi Berra said: “It’s tough to make predictions, especially about the future.”