Targeting KRAS Mutants: Advances in Drugging the “Undruggable”

KRAS is one of the most commonly mutated genes in cancers. It is present in approximately 90% of pancreatic cancers, 30%-40% of colon cancers, and 15%-20% of lung cancers. At the virtual AACR conference, Dr. Frank McCormick and Dr. Kevan Michael Shokat from the University of California San Francisco together with Dr. Stephen Fesik from Vanderbilt University teamed to discuss advances and different approaches of targeting KRAS.

Dr. Frank McCormick, UCSF Helen Diller Family Comp. Cancer Center

KRAS is major a driver of cancer; however, developing inhibitors for this protein has been a challenge because of

1) High specificity requirements (drugs that inhibit all members of the RAS family, i.e., HRAS, NRAS, and KRAS would be too toxic), and

2) It’s complex structure (the G domain of KRAS has a dynamic structure with no deep pockets described as a “squishy tennis ball”). Together, these gave KRAS the connotation of being “undruggable”.

However, scientists have been able to overcome these hurdles and they have developed molecules that target KRAS but secondary mutations in this protein lead to resistance. As a response, scientists have developed indirect approaches to target KRAS by developing molecules upstream of KRAS, such as SOS1 and SHP2 inhibitors, and by blocking the interaction with some KRAS with its binding partners, such as the Ras-dependent Raf activation.

Additionally, compounds that disrupt KRAS function in new and creative ways are being investigated. Some of these are:

• Targeting KRAS for degradation using PROTACs.
• Capturing KRAS in its inactive form in the plasma membrane using Cmpd2 (developed by Novartis).
• Using T cells to target cancer cells that express mutant KRAS.
• Using antibodies that recognize mutant KRAS to recruit immune cells to kill cancer cells.

What Do Key Opinion Leaders Think?

When asked about the prospects of developing the next generation of KRAS inhibitors, all panelists were optimistic. They all agreed that developing the next generation of inhibitors against the second mutations in KRAS would not take as long as the first generation. Now they have identified molecules that selectively bind KRAS, the basic compounds will work as templates for new compounds for other mutants. Dr. Fesik emphasized the idea of targeting multiple pockets of KRAS simultaneously.

Regarding SOS1 and SHP2 inhibitors, all panelists agreed that more research is necessary to determine the correct combinations for treatment and to determine which cancers respond more effectively to these therapies. When asked about simultaneous targeting parallel pathways to KRAS, Dr. Shokat hinted towards the progress in the field since now there are therapeutics that can target the KRAS, opening the possibility for new combinatory therapies.

Dr. Kevan Michael Shokat, UCSF

On the subject, Dr. Fesik mentioned that a better approach could be to target multiple members of the KRAS pathway, and that “one thing is clear, combination therapy is going to be the way to go”. However, they all pointed to the need for therapies effective against a secondary mutation in the KRAS as a response to treatment.

About using small interfering RNA, the panelists mentioned that siRNA had shown to be effective in mouse models, but it failed to provide any improvement in patients due to low knockdown efficiency. Delivery in humans, as well as the targeting of specific mutants, are some of the main barriers to this type of therapeutic.

However, Dr. Fesik thinks breakthroughs in delivery could make siRNA a practical treatment. He made the comparison between this technology and antibodies. For a long time, antibodies were considered a non-viable option for therapeutics, but after the introduction of humanized and human antibodies, there was an explosion of new therapeutics.

Dr. Stephen W Fesik Vanderbilt University School of Medicine

PROTAC is another exciting technology for KRAS treatment. Using the compounds developed and using them to tag the proteins for degradation could be a powerful therapeutic approach. One of the limitations is developing a ligand that is pharmaceutical useful. Using E3-ligases that are overexpressed in cancers, could add an extra layer of specificity.

With all these promising technologies on the horizon, KRAS may not be “undruggable” for much longer.

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Author

Daniel Ojeda