What’s New in Treatments that Target the MAPK Pathway in Cancer?

If you are learning about treatment options for your or your loved one’s cancer, you may have heard of the MAPK pathway. This biological feature of human cells has become an important target of numerous drugs to treat cancer. Read on to learn more about the MAPK pathway and the current status of treatments that target it.

What is the MAPK pathway?

The mitogen-activated protein kinase (MAPK) pathway is a major cell-signaling pathway. Simply put, it transmits growth signals from the outside of a cell to the cell nucleus to initiate division of the cell into two new cells. The pathway is complicated, with dozens of “players” and multiple layers of regulation, but this post will focus only on a few important proteins in the pathway that are often mutated in human cancers.

In the simplest version of the MAPK pathway, depicted in the diagram below, a protein called a receptor (most often of the type known as receptor tyrosine kinase, or RTK) binds to a growth factor (GF, or mitogen), and this activates a series of events (“signal transduction”) that ultimately results in cell division.

If a protein in the MAPK pathway becomes mutated, it could potentially lead to cancer. Cancer-associated mutations may affect several players in the MAPK family, starting with RTKs, but we will discuss here only some key proteins that convey signals downstream of RTKs (such as NRAS, BRAF, and MEK).

The MAPK signaling pathway. Image credit: Smalley and Smalley, Cancer Discovery, 2018

Mutations in proteins depicted in the diagram result in them being active even if they have not received the signal they normally should receive from an RTK bound by a growth factor. The major outcome is uncontrolled cell division (“proliferation”) that no longer requires normal stimulation by growth factors, as well as other features of cancer—migration, invasion and more.

Drugs that target the MAPK pathway typically work by inhibiting the activity of mutated proteins in order to block uncontrolled cell division and prevent tumor growth. Molecular testing can determine whether a patient has a particular MAPK mutation that can be matched with a particular inhibitor drug. To learn whether molecular testing for mutations could guide your own treatment, request free, personalized help from Cancer Commons.

Major players in the MAPK pathway : What’s new?

A variety of different drugs have been developed to target different proteins in the MAPK pathway. Here’s the latest on these proteins and the treatments that target them:

RAS family

RAS is a small family of three proteins—KRAS, HRAS and NRAS. The most frequently mutated protein in entire MAPK pathway is KRAS, and it is one of the top mutated genes in all cancers (about 19%). In particular, KRAS is involved in 90% of pancreatic, 40–50% of colon, and 20–30% of lung cancers, to name a few. NRAS is most often found in melanoma (15–30%), but is also seen at a very low frequency in various other cancers. HRAS is mutated with appreciable frequency in head and neck cancer, in particular oral cancers (up to 35%), and in some rare types of lymphoma.

Until recently, mutated RAS proteins were considered to be “undruggable” because the particular structure of these mutated proteins makes it difficult to design drugs that inhibit them. This has changed now, to a degree. There are now drugs that target one particular mutation in KRAS known as G12C. KRAS G12C is not the most frequent mutation encountered in KRAS, but it is still found in 14% of lung cancers. In clinical trials, two new drugs known as AMG 510 and MRTX849 have shown efficacy in treating lung cancer harboring the KRAS G12C mutation. They have also shown some promising activity in other types of cancer with this mutation.

The drug of note for HRAS-mutant cancers is tipifarnib, whose mode of action is entirely different form that of KRAS-targeting drugs. Tipifarnib disrupts the association of HRAS with the cell membrane, which is needed for HRAS activity. It has produced promising results for head and neck cancers in clinical trials, and the U.S. Food and Drug Administration (FDA) has placed it on a fast track to approval for treatment of certain aggressive T-cell lymphomas.

There are no drugs yet that target NRAS mutations directly (more on that later).

BRAF

The BRAF protein is mutated in 60–70% of melanoma cases, but also with a much lower frequency in colon, lung, thyroid and some other cancers. There are highly active FDA-approved drugs that inhibit BRAF proteins that are mutated in a particular part of the protein called position V600 (the predominant site of mutation). The standard of treatment for people with BRAF V600-mutant melanoma is dual inhibition of BRAF and its downstream partner protein MEK, with FDA-approved drug combinations targeting both BRAF and MEK (dabrafenib and trametinib or encorafenib and binimetinib). This approach is also effective in non-small cell lung cancer (NSCLC) with BRAF V600 mutations, but treatment of BRAFmutant colon and thyroid cancers requires additional drugs.

BRAF mutations are sometimes encountered in positions other than V600, and cancers with these more rare mutations are often not responsive to the available inhibitors of BRAF V600 and MEK.

MEK1/2

MEK mutations are seen in a variety of cancers, but with a low frequency. Still, because the MEK protein plays an important role in the MAPK pathway, there are several MEK inhibitors already approved by the FDA, and more are in development to target MEK in cancers with other mutations in the MAPK pathway (as mentioned above for BRAF-mutant melanoma and NSCLC).

ERK1/2

The ERK protein is rarely mutated in cancer. But ERK is an ultimate player in the MAPK pathway, because it transmits the signals it receives directly to the cell nucleus, where it activates a transcriptional program leading to proliferation. This makes ERK a desirable target in trying to curb the activity of MAPK in cancer because, at least in theory, if ERK is inhibited, the cancer-promoting effects of the upstream players (e.g., KRAS, BRAF, or MEK) could be mitigated.

The other reason for targeting ERK is that, as mentioned above, BRAF mutations are not confined only to the V600 position in this protein, and no inhibitors yet exist to target these more rare mutations in BRAF.

Finally, inhibition of RAS, BRAF, and MEK most often eventually leads to development of resistance, meaning that the drugs stop working and the cancer continues to grow. So, other ways to inhibit the activity of the MAPK pathway are needed.

That explains why ERK is a desirable target. But it is not an easy target. There are, or rather were, at least ten ERK inhibitors in clinical development, and most of them showed good activity in laboratory experiments in cancer cells and animals before being tested in clinical trials.

However, several of these ERK inhibitors were dropped from development for reasons that had to do with either lack of preliminary evidence of activity or poor tolerance by patients, or both: ASN-007, CC-90003, GDC-0994, and KO-947.

Several ERK inhibitors are still in clinical trials—but only in combinations with other targeted drugs because they did not produce encouraging results on their own. These are: LY3214996, which, on its own, induced improvement (responses) only in 7 of 51 patients (14%); MK-8353, which had a 12% response rate, and only in patients with BRAF V600 but no KRAS or NRAS mutations; and LTT-462, which showed limited clinical activity in patients with MAPK pathway mutations.

There are newer ERK inhibitors in early trials: ASTX029 and JSI-1187, with results pending.

An ERK inhibitor called BVD-523 (or ulixertinib) is the likely frontrunner now. It has completed a phase I trial in which responses were seen in patients with various cancers harboring NRAS and BRAF mutations, including melanoma, NSCLC, and colorectal cancers. Now, BVD-523 is in trials for cancers that have the atypical BRAF mutations G469A/V, L485W, or L597Q, or other MAPK pathway mutations. It is also available on an “expanded access” basis in the clinical trial NCT04566393.

What does this mean for my cancer treatment?

Drugs that target MAPK-pathway proteins have clearly made a huge impact in the world of cancer treatment, and more options are on the horizon. These drugs are a great example of personalized cancer treatment in which patients receive particular drugs based on the distinct features of their cancer. However, because patients can develop resistance to many MAPK-pathway drugs, new drugs and combinations are needed.

If you or a loved one have metastatic cancer, and you want to know if any of these treatments are a good fit, I encourage you to request a free Cancer Commons treatment options report.

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