While targeted therapies have emerged in the past decade to improve treatment of non-small cell lung cancer (NSCLC) with some types of driver mutations (such as EGFR and ALK), lung adenocarcinomas with KRAS driver mutations have been notoriously difficult to study and treat.
KRAS is just one member of a large family of proteins, called RTKs (receptor tyrosine kinases) that span from the surface of the cell into the cell’s interior. This positioning allows RTKs to detect signals (such as hormones or proteins) outside the cell and transmit signals to the inside of the cell. These signals trigger a variety of cellular behaviors, including the regulation of cell growth.
Specific mutations in RTKs can significantly alter this signaling and drive tumor growth. There are many different subtypes of KRAS driver mutations, but the KRAS G12C driver mutation is the most common subtype -- appearing in approximately 12%-15% of patients with NSCLC.
LUNGevity Foundation spoke to Kathryn Arbour, MD, medical oncologist at Memorial Sloan Kettering Cancer Center and recipient of LUNGevity’s Career Development Award in 2020, to learn about more recent advances in treating KRAS-mutant lung cancer.
LUNGevity Foundation: Why have we had such difficulty targeting KRAS in the past and what happened to help researchers unlock KRAS treatment options?
Dr. Kathryn Arbour: KRAS was long considered “undruggable” with the only effective treatments being chemotherapy and more recently immunotherapy. In the past, research efforts focused on targeting signaling pathways downstream of KRAS. Unfortunately, these approaches were largely ineffective and rarely led to meaningful control of the cancer for patients. Then, in 2013, researchers identified the binding pocket of the KRAS G12C protein. Identifying the binding pocket was a big step that enabled the development of a new class of drugs -- direct KRAS G12C inhibitors, or KRAS G12Ci. These drugs can shut off the RAS pathway that signals the cancer cells to grow in an uncontrolled fashion. These drugs demonstrated success in early-phase clinical trials with 30-40% of lung cancer patients having substantial decrease in the size of the tumors. This has been a significant breakthrough for our patients.
LF: Are there now therapies available to treat lung adenocarcinoma with KRAS G12C mutations?
KA: Yes – the U.S. Food and Drug Administration (FDA) has approved the use of sotorasib for lung adenocarcinoma patients with KRAS G12C mutations. Recently, at the 2022 AACR conference, two-year data showed continued improvements for patients taking sotorasib compared to those using chemotherapy.
In addition, another drug, adagrasib, has been designated a breakthrough therapy by the FDA, and it also has shown promising results and was recently presented at the 2022 ASCO conference. Many others are also being studied. These KRAS G12Ci drugs have similar mechanisms of action that involve binding the KRAS protein in the GDP-bound state, rendering it inactive and causing tumor shrinkage.
LF: Do the KRAS G12C tumors develop drug resistance to these treatments?
KA: Like targeted therapies developed for other driver mutations found in lung cancer, research suggests that even after a period of successful tumor shrinkage, the tumors are likely to develop resistance to the treatment and begin to grow again.
Many researchers, including myself, are working to understand the reasons for this resistance and to develop treatments to overcome this resistance. As part of these collaborative efforts, which were published in Nature and The New England Journal of Medicine, we now have data on the mechanisms of resistance for patients who are treated with G12Ci therapy alone.
We think it is likely that the tumors develop ways to get around the G12Ci treatment through another signaling pathway, such as increased signaling through various RTKs.
LF: Tell us more about your LUNGevity-funded research.
KA: There are two important elements to the research project. First, we have built a library of patient-derived xenografts or mouse models. We take samples from patients before treatment, during treatment, and, if applicable, when the tumor starts shrinking. These patient biopsy samples are processed and placed in mice to give us a quick and in-depth way to identify effective therapies and to study tumors from the same patient as they evolve through the course of treatment. I hope that this library becomes a foundational resource to help collaborators around the world quickly identify therapies to benefit patients.
The second aspect of this research is the ongoing clinical trial. We have an open clinical trial to look at the effects of combining G12Ci treatment with a SHP2 inhibitor in order to block one important RTK pathway. We predict this approach will potentially decrease or prevent resistance to treatment with G12Ci, enabling treatments to be more successful at controlling cancer for a longer period of time. Through this trial, we have access to patient biopsies and blood samples to help us understand the effects of this treatment combination.
We’re so thankful to patients and their families for being willing to be a part of this research. By allowing us to access their biopsy samples and blood samples, they are giving us the opportunity to understand their individual tumor, which will help advance the field for all patients with KRAS-mutated lung cancer.
LF: What are your future plans for this research?
KA: In the future, we will use other advanced techniques, such as single-cell sequencing, to continue to optimize and deepen our understanding of the mechanisms of action in KRAS-mutant tumors. We aim to develop a timeline for how these tumors evolve so that we can understand how the resistance evolves.
Our goal is to use these learnings and the library of patient-derived xenografts to maximize the number of patients that can benefit from treatment. I hope we learn lessons from our experiences with KRAS G12C mutant lung cancer so we can apply those lessons to other KRAS-mutant lung cancers. I think this is only the beginning for targeted therapy for KRAS-mutant lung cancers.
LF: How has this award impacted your career?
KA: This award has given me the freedom to focus on academic research and to develop a specialization in KRAS-mutant lung cancer, both within my institution and beyond. It provides me with the validation to go forward, and it gives me time and space to work with translational collaborators.
I feel so grateful to have such wonderful partners and incredible mentorship here at Memorial and through the LUNGevity award.
LF: What are your goals for your career?
KA: My goal is to be a successful translational collaborator. Running clinical trials and seeing patients is incredibly important and serves as the foundation for our work. I like guiding patients through treatment and also empowering patients with opportunities to improve treatment options for themselves and for others.
When we have funding (like this LUNGevity award) to help deepen our understanding of KRAS-mutant lung cancer, those conversations with patients are so much more rewarding. I love being able to say that we are actively working to make things better and then inviting patients to actively participate in the process, too. That’s incredibly meaningful as a physician.
LF: Anything you’d like to add?
KA: Current advancements in targeted therapies in KRAS mutant lung cancer have been decades in the making and I truly feel privileged to be conducting clinical trials at such an important time for patients. I am proud to be a part of the efforts that are ongoing everywhere to improve these therapies in a collaborative approach across different academic institutions. It’s very meaningful for me to be a part of the broader KRAS community that is examining how best to utilize these therapies to improve outcomes for lung cancer patients worldwide.