What Is KRAS and Why Is It So Hard to Target in Cancer?

Asfar S. Azmi, a professor at Karmanos Cancer Institute and Wayne State University, explained how KRAS went from an “undruggable” target to one now being treated with new therapies.

KRAS was difficult to target because its structure lacks the deep binding pockets most drugs need. Researchers later found that KRAS switches between an “on” state, which promotes cancer, and an “off” state. During this transition, a temporary opening appears, giving scientists a way to design drugs to target it.

This discovery led to the first KRAS inhibitors, particularly in non-small cell lung cancer. Current KRAS G12C inhibitors show response rates of about 30% to 40% and a median progression-free survival of about six months. For patients, this means some may see tumor shrinkage and symptom relief, though benefits may be temporary.

Resistance remains a challenge. Cancer cells can activate alternate pathways, rely on upstream signals like EGFR or develop new mutations such as G12D or G12V to bypass treatment.

To address this, newer therapies are expanding beyond G12C. Pan-KRAS and pan-RAS inhibitors aim to target multiple mutations at once. One investigational drug, RMC-6236, has shown an overall survival of 13.2 months in previously treated pancreatic cancer, compared with about six months historically.

Combination strategies, including pairing KRAS inhibitors with EGFR inhibitors, chemotherapy or immunotherapy, are also being explored to improve outcomes.

Looking ahead, KRAS-targeted therapies may become a standard part of care, with broader inhibitors and new approaches designed to keep the protein in its inactive state.

CURE: KRAS mutations have long been considered difficult to target. What changed in our understanding that finally made KRAS a druggable target?

Azmi: This was one of the central and most elusive targets in cancer. Researchers knew a lot about KRAS, but it was never considered a druggable protein. Most proteins used as drug targets have deep pockets where drugs can bind. KRAS, however, has a unique structure. It is very circular, like a golf ball, with shallow ridges and no deep pockets for drugs to attach.

Researchers took a closer look at its structure and found that KRAS switches between an “on” and “off” state. When it is on, it promotes cancer. When it is off, cancer growth stops. In most patients with KRAS mutations, the protein remains in the “on” state. Chemists discovered that during the transition between the off and on states, a temporary opening appears. That opening became a target for drug development.

This marked the first step in targeting KRAS. Since then, further research has identified additional binding sites, including ways to target both the off and on states. Advances in technology have helped uncover these previously hidden pockets, leading to the development of multiple new drugs.

Current KRAS G12C inhibitors in non-small cell lung cancer show response rates of about 30% to 40% and a median progression-free survival of around six months. How should patients understand what these numbers mean in practical terms today?

In practical terms, these numbers mean that a meaningful benefit is seen in a portion of patients. Some will experience tumor shrinkage, symptom improvement and better quality of life. However, not all patients will respond, and for some, the benefit may be temporary.

A 30% to 40% response rate means that tumors shrink in about that percentage of patients. Progression-free survival of six months means the cancer is controlled for about six months before it may begin to grow again. These results reflect first-generation KRAS inhibitors. Newer drugs are being developed that may improve response rates and extend how long the disease remains controlled.

Resistance remains a major challenge with KRAS-targeted therapies. What are the most common ways cancer cells adapt or become resistant to these treatments?

KRAS is a central protein that drives multiple cancer-related pathways. When one pathway is blocked, others can become activated. In addition, upstream proteins such as EGFR can continue to fuel KRAS activity.

Cancer cells can also develop genetic resistance. For example, a tumor initially driven by a KRAS G12C mutation may shift to other mutations such as G12D or G12V. At the same time, parallel signaling pathways, including EGFR, PI3K and MAPK, can reactivate and allow the cancer to grow despite treatment.

These challenges have led to the development of combination strategies that aim to block multiple pathways or mutations at once.

Many cancers are driven by KRAS mutations beyond G12C and still lack targeted options. Where is the field right now in addressing these harder-to-treat mutations?

KRAS G12C is most common in non-small cell lung cancer and is rare in pancreatic cancer. In contrast, KRAS G12D is found in 30% to 40% of pancreatic cancers. First-generation drugs targeted only G12C.

Newer therapies are now being developed to target a broader range of KRAS mutations. Pan-KRAS inhibitors are designed to target multiple KRAS variants, including G12C, G12D and G12V. Beyond that, pan-RAS inhibitors target the entire RAS family, including KRAS, HRAS and NRAS.

One such drug, also known as RMC-6236, has shown encouraging results in pancreatic cancer, including an overall survival of 13.2 months in previously treated patients. Historically, survival in this setting has been around six months, suggesting a meaningful improvement.

Combination therapies are increasingly being explored alongside KRAS inhibition. What kinds of combinations are showing the most promise and why?

Some combinations have already been approved. In colorectal cancer, a KRAS G12C inhibitor combined with an EGFR inhibitor has received regulatory approval. In pancreatic cancer, combinations are still under investigation.

Researchers are studying combinations with chemotherapy, EGFR inhibitors and other targeted agents. There is also interest in combining KRAS inhibitors with immunotherapy, as KRAS targeting may enhance anti-tumor immune responses.

Preclinical studies have also explored triple combinations targeting KRAS, EGFR and additional escape pathways, showing strong results in models. These strategies aim to block both the primary driver and the pathways cancer cells use to bypass treatment.

Looking ahead, what would success look like for KRAS-targeted therapy over the next five to 10 years?

Recent results suggest that RAS-targeted therapies could become a standard part of treatment. Pan-RAS inhibitors may eventually replace chemotherapy in some settings, including second-line and potentially first-line treatment.

In the future, patients may routinely undergo genomic testing to identify RAS mutations and guide treatment selection. Combination therapies may further improve how long responses last and extend survival.

New approaches, including RAS catalytic inhibitors that keep the protein in its inactive state, are also emerging. These are still in early development but may represent another step forward.

Transcript edited for clarity an conciseness

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