Intratumoral heterogeneity may explain why small cell lung cancer ‘becomes almost pan-resistant’
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New study findings may provide the key to overcoming treatment resistance in small cell lung cancer, according to researchers at The University of Texas MD Anderson Cancer Center.
In a study led by Lauren Averett Byers, MD, associate professor of thoracic/head and neck medical oncology in the division of cancer medicine at MD Anderson, researchers found that chemotherapy appears to trigger increased intratumoral heterogeneity, which leads to the development of multiple resistance mechanisms.
“As a physician scientist who treats a lot of patients with small cell lung cancer, I’ve noticed that even though this type of cancer responds very rapidly when patients are first treated with chemotherapy or radiation, for example, the cancer very rapidly develops resistance,” Byers said in an interview with Healio. “Often, within a few months, the cancer recurs. At that point, very, very few patients respond to further treatment; it becomes almost pan-resistant.”
Treatment has changed minimally over the past several decades for small cell lung cancer, which comprises 14% of all lung cancers. Noting the scarcity of post-relapse tissue samples, Byers and colleagues developed models of small cell lung cancer from circulating tumor cells collected through liquid biopsy. They conducted single-cell RNA sequencing to identify differences in gene expression between cells from chemotherapy-resistant and chemotherapy-sensitive tumor models. Additionally, they performed single-cell sequencing on circulating tumor cells extracted from a small amount of blood from a patient before treatment, during treatment and after recurrence.
Byers spoke with Healio about the potential mechanisms of resistance in small cell lung cancer and what her findings could mean for future treatment of the disease.
Question: What did you hope to learn from this study?
Answer: In my lab and in our group, we were very interested in trying to understand why small cell lung cancer is so resistant and why the disease is so different after it has been treated than it was before any therapy. This is a fast-growing cancer, and a lot of data show that it can undergo different epigenetic changes. So, we thought maybe it’s evolving very rapidly. Our first idea was that there were resistant cells to begin with, starting with the cancer, and that these bad actors became apparent after the chemotherapy-sensitive cells were killed. The other possibility we considered was that under the pressure of treatment, the tumor cells were able to evolve to escape it.
Q: How did you conduct the study?
A: We had a unique opportunity to study drug resistance in small cell lung cancer by leveraging tumors we had grown in the lab from patients’ circulating tumors (circulating tumor cell-derived patient xenografts), as well as a new technology — single-cell sequencing, or single-cell RNAseq — to discovery what genes were turned on in individual cancer cells. We started by making new models of small cell lung cancer from circulating tumor cells. We would collect blood from a patient and enrich for circulating tumor cells, which we would grow in a mouse into a tumor. An advantage of that was that we captured the heterogeneity, as well as the cells that were actively metastasizing in the circulation. Some of those models were established from patients who were still chemotherapy sensitive, whereas others were from patients whose cancers had developed resistance.
Q: What did you find?
A: The tumors from patients who developed resistance had much more heterogeneity than those that were chemotherapy sensitive. So, in those resistant tumors, there were multiple different populations of cancer cells. Those groups of cells could have different resistance mechanisms or different drug targets that are turned on at the same time and within the same tumor. We then did experiments in the lab in which we treated a tumor in a mouse model that was still sensitive to chemotherapy. We did a kind of before-and-after and saw the same thing happening that we’d observed in those therapy-resistant patients: the tumors went from being relatively similar in terms of the cells and which genes were activated on a cell-by-cell basis to these very different, very diverse groups of cells. Different populations turned on different types of resistance mechanisms at once.
We also did the single-cell analysis of circulating tumor cells directly from a patient’s blood, before she had treatment and after the cancer recurred. We saw the same thing. Before the patient started treatment, a few cells were different from the others, but not many. After treatment, there were multiple different groups and different resistance mechanisms. So, we think the cancer cells are rapidly evolving, but doing so in many different directions to try to escape treatment or in response to the pressure applied by the treatment. I think this can explain a major reason why when small cell lung cancer relapses, only a small number of patients respond to chemotherapy or other targeted therapies in trials.
Q: What are your plans for studying this phenomenon further?
A: We have a translational research program at MD Anderson, through which we’re trying to learn as much as possible from our patients on our clinical trials.
The next step will be more of this type of profiling, to follow patients longitudinally across a larger group. We want to see how their cancers are changing. Then, we would look for the best way to either prevent this evolution or find some sort of Achilles heel in the cells — maybe something that leverages a certain vulnerability, even independent of which pathways they might be using to grow.
We already have clinical trials in which we’re exploring whether, instead of waiting until the cancer relapses and starts growing again, we can bring in some of our most promising drugs earlier in some form of maintenance treatment. Right now, the standard of care for small cell lung cancer is a combination of chemotherapy and immunotherapy. We want to see if we can bring these combinations in before the cancer has relapsed, when it hasn’t yet evolved in multiple directions.
We’re fortunate that there’s a major effort now by the NIH and NCI to make progress in small cell lung cancer. I think one of the major challenges has been acquiring samples from patients with relapse, so we can understand what was contributing to that and how we can address it. Techniques like single-cell analysis and studying cancer cells directly from a blood sample provide a real opportunity for learning about how this cancer changes over time. Having translational research programs where we can collect patient samples and learn directly from our patients is transformative in terms of making progress against this cancer. – by Jennifer Byrne
Reference:
Stewart CA, et al. Nat Cancer. 2020;doi:10.1038/s43018-019-0020-z.
For more information:
Lauren Averett Byers, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.
Disclosures: Byers reports advisory board roles with AbbVie, AstraZeneca, BerGenBio, Bristol-Myers Squibb, Genmab, Genentech, Merck, Pharma Mar SA, Pfizer and Sierra Oncology, and research support from AbbVie, AstraZeneca, Genmab, Sierra Oncology and Tolero Pharmaceuticals.