KRAS mutations in lung cancer: Are we close to targeting the untargetable?

Upal Basu Roy, MPH, PhD

The success we have seen with targeted therapeutics for EGFR-mutated or ALK-rearranged lung cancers has not been demonstrated in KRAS-positive tumors. I am really excited that that’s changing. We are finally at the cusp of promising new treatment approaches directed toward the KRAS gene mutation. Some of these approaches are already moving toward clinical trials.

– Pasi Jänne, MD, PhD

Dr. Pasi Janne

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Thanks to advances in molecular biology, researchers have been able to identify driver mutations—changes in the sequence of DNA—that fuel the growth of NSCLC cells. The KRAS gene is one such gene, which is mutated in almost 25% of adenocarcinoma patients. Other mutations in lung adenocarcinoma occur in other genes, such as the EGFR, ALK, and ROS1 genes. Currently, targeted therapies that block the effect of some of these mutations are either approved or in clinical development. Mutations in the KRAS gene, however, have been difficult to target.

I sat down with Pasi Jänne, MD, PhD, from the Dana-Farber Cancer Institute/Harvard Medical School to discuss the latest developments in our understanding of the biology of the KRAS gene mutation and how these are translating into clinical progress. Dr. Jänne is director of the Lowe Center for Thoracic Oncology and co-leader of the Stand Up To Cancer Lung Cancer Dream Team, which is developing better therapeutics for KRAS-positive lung cancers.

LUNGevity Foundation: How has our understanding of the KRAS gene changed over the past ten years?

Pasi Jänne: Mutations in the KRAS gene were among the first alterations to be discovered in lung cancer, in the 1990s. However, we were unable to target this protein because of its complex biology.

Now we know that there can be mutations in different parts of the KRAS gene. In lung cancer, for example, we find mutations such as G12C and G12V. These mutations change the sequence of the KRAS protein, which then behaves quite differently than the normal KRAS protein. More importantly, we have learned that these different mutations are also unique from one another—a G12C mutation behaves very differently than a G12V mutation.

Another development in this area is that KRAS mutations typically co-occur with a mutation in another gene, such as TP53 or LKB1, and these combinations likewise behave differently from each other.

The KRAS pie is being sliced even further, and this knowledge is helping us develop better therapies for our patients.

LF: What are some of the new treatment approaches to targeting KRAS mutations?

PJ: Our understanding of the biology of this gene has led us to use two approaches.

We are now developing drugs that block specific mutations in the KRAS gene. A targeted agent that specifically blocks the G12C mutation has shown promising results in laboratory studies. I am hopeful that this drug will move into a clinical trial by the end of this year. This is an enormous development; if this works, we might have the first targeted agent for KRAS. Around 50% of KRAS-positive lung cancers contain the G12C mutation. So this drug, if effective, will provide benefit to a large survivor population.

Also, the KRAS protein gives out “don’t stop growing” signals to the cancer cells by talking to other proteins such as MEK. Our second approach has been to use drugs that block these downstream proteins and block communications to the cancer cell. This approach has been only moderately successful so far because the cancer cells become resistant to MEK inhibitors. Now that we know this, we are trying combination targeted therapies that will take care of the resistance to MEK inhibitors. These combinations look really promising in preclinical studies. A clinical trial testing these approaches is on its way.

LF: The FDA just approved combination immunotherapy for patients with metastatic non-squamous lung cancer. Are there any immunotherapy approaches for KRAS-positive lung cancers?

PJ: Well, we have treated patients with KRAS-positive lung cancers with immunotherapy. Their response is very similar to that of the part of the lung cancer survivor population that is not EGFR- or ALK-positive, where immunotherapy hasn’t been very effective. This is exciting, and has led to immunotherapy and targeted therapy combination trials. We are waiting for the readout of these trials.

Which patients will derive the most benefit from immunotherapy? Could combination therapy be an option for patients where immunotherapy doesn’t work? These are the questions that keep me awake at night!

Through the Stand Up To Cancer project, we are working with top scientists in multiple institutions to leverage all our knowledge and expertise to develop customized treatments for KRAS-positive lung cancer patients. We are definitely moving in the right direction!


Dr. Basu Roy is LUNGevity's Director of Science Communications and Programs. Dr. Upal Basu Roy

Category: 
Mutations
Targeted therapy

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