KRAS, the ‘damned’ cancer protein that is the target of research for modern treatments

When a cell undergoes a mutation in a proto-oncogene – a gene that in its normal state regulates cell growth and division – and becomes an oncogene, it can start transforming into a tumor cell.

If the immune system detects this mutated cell and is able to kill it, or if the cell itself detects the error and commits suicide, it poses no threat.

But if that mutation adds up to other changes in the cell’s genome that block apoptosis (or cell suicide) and allow it to go unnoticed by the immune system, cancer will appear.

One of the oncogenes that is frequently mutated in various tumors, including lung, colorectal, and pancreatic cancer, is KRAS (short for mouse sarcoma Kirsten virus homologous oncogene).

Priority target for 40 years

The protein encoded by this gene is part of the RAS oncoprotein family (HRAS, NRAS and KRAS). Of the three, KRAS is the most frequently mutated in cancer: it is present in approximately 1 in 4 patients.

For this reason, it has been one of the main therapeutic targets in the fight against this disease since its discovery in 1982.

Mutations in the KRAS protein are concentrated in one of its constituent molecules, amino acid 12 –although it can also occur in 13 and 61–, and trigger permanent activation of the protein.

As a consequence, more than ten signaling cascades involved in tumor proliferation and metastasis are activated.

Since its discovery, several strategies have been studied to try to block the activity of the mutant KRAS, but doing so directly has revealed great complexity, both due to the characteristics of the protein itself and the high toxicity generated by the drugs.

Therefore, the approval of KRAS inhibitors as a treatment has been awaited for four decades.

Finally the first drugs arrive

In May 2021, the first KRAS inhibitor received approval from the US Food and Drug Administration (FDA). It specifically works against the KRASG12C mutation for the treatment of lung cancer and is branded as Sotorasib (AMG510).

Months later, in January 2022, the European Medicines Agency (EMA) also approved Sotorasib.

In addition, the FDA is evaluating the approval of another inhibitor against the same mutation, Adagrasib (MRTX 849), which may be marketed soon.

The G12C mutation (which consists of the alteration of the amino acid glycine at position 12 by a cysteine) is the most frequent in patients with non-small cell lung cancer with mutated KRAS, who represent approximately 13% of all patients with this type of cancer .

It is also present in some colorectal and pancreatic cancer patients, although in a much smaller percentage.

Currently, there are more than 100 clinical trials in patients with lung and colorectal cancer to test drugs that block KRAS or the proteins related to its activity.

One of the important targets to stop the effect of this oncoprotein is the epidermal growth factor receptor (EGFR), which is the mitogen responsible for activating KRAS. In other words, the signal that activates the protein.

alternative targets

Although the mutated KRAS protein has been a difficult target from a pharmacological point of view –becoming considered inaccessible for several decades–, the proteins related to its activation have been the subject of numerous studies as alternative and more accessible targets.

These works made it possible to expand the arsenal of experimental drugs to inhibit this very lethal oncoprotein and its collaborators.

1. Inhibitors of proteins involved in KRAS activation.

SHP2 is a phosphatase (a type of enzyme) known to promote tumor cell survival.

Although inhibitors developed against this molecule have shown limited effectiveness as a single treatment, their combination with therapies targeting other proteins has improved their effectiveness.

Another molecule under study is SOS1, which plays a key role in activating KRAS. Its inhibition would decrease the activity of the protein and favor the remission of tumor growth.

2. KRAS-activated protein inhibitors.

KRAS activates cell signaling pathways that allow tumor cells to survive, proliferate and invade other tissues (metastasis).

Blocking these pathways by inhibiting some of the proteins involved, such as ERK or mTOR, could allow control of the pro-tumor activity of KRAS.

In other words, if we attack KRAS directors or messengers, we could nullify their effect. But, just like in action movies, when the protagonist tries to defuse a bomb, you have to be careful with the wire that will be cut.

Blocking the proteins involved in KRAS signaling can have important side effects, as these proteins are also relevant in other physiological processes.

The fight goes on

The main current challenge is to improve the effectiveness of already developed inhibitors.

The combination between them, or with different antitumor drugs, could help not only to develop more efficient therapies, but also to avoid drug resistance that occurs when using a single therapeutic agent.

Another fundamental challenge is to search for new inhibitors that make it possible to silence KRAS, regardless of its specific mutation.

One of the most promising therapeutic strategies is immunotherapy – that is, the use of the patient’s own immune system to attack tumor cells that carry one or several mutations.

This is the case with vaccines, which we are also working on in our research group, or with T-cell therapy (CART), that is, the patient’s white blood cells are reprogrammed to selectively attack malignant cells.

And finally, gene therapy using CRISPR/Cas9 technology, aimed at silencing or repairing the mutated gene, could also corner this very elusive oncoprotein.

The development of effective drugs to block KRAS and related signaling pathways will be a very important milestone in the treatment of many tumors.

It could even cure some types of cancer that currently have a poor prognosis, such as pancreatic cancer.

Rosana Simón Vázquez holds a PhD in biochemistry and molecular biology. Researcher in the area of ​​nanomedicine and immunology at the University of Vigo, Spain.

Lara Diego González is a research support researcher. Transplantation and Autoimmunity Group at the Marqués de Valdecilay University Hospital, Spain.

This article originally appeared on The Conversation academic news site and is republished here under a Creative Commons license. Read the original version (in Spanish) here.

This text was originally published here.