Anticipating NRAS Resistance

Every medical treatment is a tradeoff between benefit and side effect – and part of any physician’s job is to determine whether or not the downsides to a given treatment are a worthwhile price to pay for its potential health benefits. One factor in the therapeutic equation is resistance: what good is a treatment if the patient’s disease can resist its effects?

Establishing whether or not a disease exhibits resistance mechanisms is especially important when it involves patients whose illnesses could be fatal if left untreated. A team at The University of Texas MD Anderson Cancer Center, led by Lawrence Kwong, decided to tackle this issue in patients with NRAS melanoma. To learn more, we spoke with Lawrence Kwong, Assistant Professor in the Department of Translational Molecular Pathology at MD Anderson.

Why focus on NRAS melanoma?

NRAS melanoma, which represents about one quarter of melanomas, currently has no approved therapies specifically for it, unlike BRAF melanomas. Even with the recent success of immune checkpoint blockade therapies such as anti-PD1 and anti-CTLA4, at least half of NRAS patients who receive such treatments will eventually relapse and require other therapeutic strategies.

My previous work indicated that MEK plus CDK4/6 inhibitors would be efficacious for NRAS melanoma, and early clinical trial results show promise. Our current study anticipates that some NRAS melanomas may exhibit resistance to this therapy, but also potentially informs other clinical trials of the same therapy in RAS-mutant lung, pancreatic, and colon cancer.

What does your research mean for patients?

Our results mean that, even before going in for therapy, a cancer patient might already harbor a small percentage of cells that will eventually cause drug resistance. However, current clinical tests might miss these – either because the test resolution is too low, or because they typically look at only one part of the tumor, meaning that they might miss resistant cells hiding in another part. Fortunately, we already know many of the common resistance-causing melanoma mutations for both targeted therapies (such as BRAF and MEK inhibitors) and immune therapies (such as anti-PD1 and anti-CTLA4), meaning that we at least know what to look for. If we can find out beforehand whether a patient already harbors resistant cells, we could possibly devise a course of therapy to pre-empt that resistance – when and if we can prove that to be safe and effective. In the meantime, our study lets other researchers know how important it is to use high-resolution sequencing assays and to test multiple regions of a tumor to find such rare, pre-existing mutations. Building up a body of data on these will be critical to moving it into the clinic.

What’s next for your work?

Our lab will continue to look at the large store of tumor samples available at MD Anderson across different cancer types and drug treatments to understand how resistance occurs over time. We are also creating a model in Petri dishes to figure out how cell populations evolve over long stretches of drug treatment, as a way to understand which cancer cell types are most relevant to the clinical setting. For example, other labs have shown that melanoma cells that express a protein called AXL show intrinsic tolerance to a wide array of drugs. However, it is unclear exactly how this cell type contributes to full-blown resistance, as many drug-resistant melanomas do not show high AXL expression. Some have suggested that these cells might provide temporary drug resistance before more permanent resistance mechanisms are acquired; others that they are relatively unimportant in generating permanent resistance compared with pre-existing drug-resistant cells. We are planning experiments to specifically test these different hypotheses; it’s possible that both are correct in different contexts.

What more can be done?

I once took a tour of the pathology room at MD Anderson and was amazed by the volume, efficiency, and quality of the work being done. I also saw that large chunks of tumors were being discarded, which was clearly a practical necessity. Looking back on that, in light of the current study, it would be wonderful if researchers and clinicians communicated more often; that might lead to specific instances in which extra tumor pieces could be saved for multi-region analysis. I am personally striving to make those connections more often, and I would encourage anyone reading this on either side to reach across as well.