Understanding (and Overcoming) Treatment Resistance

This is such rewarding and important work and MRA helps make that possible.”


Targeted and immune-based therapies have transformed the melanoma field and have led to substantial improvement in overall patient survival. However, too many people still don’t respond to existing treatments, termed primary resistance, and significant portions of patients who do respond initially develop acquired resistance, meaning a therapy works initially but later fails.

The challenges posed by treatment resistance, are being tackled by many melanoma researchers across the globe, including four-time MRA-funded investigator Roger Lo, MD, PhD. Lo currently serves as Professor of Medicine, Professor Molecular & Medical Pharmacology, Associate Chief of Dermatology, and Director of the Melanoma Clinic in Dermatology at UCLA. He and his lab are currently working to understand how treatment resistance develops at a molecular level and if the location of the metastatic tumor in the body influences this process.

This is important because Lo hopes that by understanding the mechanisms at work during treatment resistance, he and his team can design treatment regimens that can breakthrough and overcome these molecular adaptations. Currently, patients who develop resistance to both CTLA-4 + PD-1 combination immunotherapy and/or BRAF/MEK targeted therapy represent an urgent area of unmet medical need.

However, doing this will require:

  • A better understanding of how tumors become resistant to existing therapies,
  • Identifying patients who will and those who will not respond to treatment, and
  • Developing new and improved treatments to defeat melanoma resistance.

To address this, Lo and his team are looking at how resistance occurs in different parts of the body, in different organs, and how this process adapts in various organ systems — with a special focus on the brain. These are important research aims because right now, we don’t fully understand why, for example, a patient may develop treatment resistant tumors in a specific organ, but nowhere else. Understanding the factors at play, could give important insight into developing future treatments.

This is critically important for patients facing brain metastasis, otherwise known as “brain mets.” These are an all-too common and difficult-to-treat problem in patients with advanced melanoma. Lo explains that therapies that work elsewhere are often not as effective in the brain and that tumor resistance, especially in the brain, ultimately proves fatal for many patients. Through this work, Lo and his team are trying to uncover novel combinations and sequences of therapies that will work even better for patients facing brain mets and, to ultimately, extend patient survival.

“There is a vast amount of biology to be understood with regard to this disease,” explains Lo. “But I think the most practical and translatable approach is to study how the cancer adapts to the therapies. We can let the biology of resistance in the clinic teach us about the most critical aspects of melanoma biology. We want to find additional targets in order to develop combinations, sequencing regimens, and different strategies that involve well-established, FDA-approved therapies, plus more, in order for us to deliver the most realistic near-term cures.”

In a manuscript published in August 2021 by the journal Cancer Cell, Lo reports in his preclinical studies on mice, that starting with two-doses of PD-1/L1 based immunotherapy (with or without ipilimumab) followed by combining BRAF/MEK inhibition leads to a superior approach — more effective than either approach on its own or the use of both simultaneously.¹

In his mouse models, this combination maximizes antitumor immunity and efficacy, including for controlling brain mets. Based on his findings, Lo urges clinical trials be designed to see if his findings bear out among people.

“What we did was test in animal and other models of metastases different ways of combining and sequencing therapies to find the regimen that works best. On top of that, we found the mechanism of why the optimal regimen works in contrast to the traditional way of doing one treatment until it fails and then moving on to another,” says Lo.

“In melanoma in particular, we were surprised by how well this regimen suppresses treatment resistance,” Lo said. “In a metastatic model where the majority of animals die within a couple of weeks with brain metastases, the regimen we proposed afforded survival with complete responses that extend routinely to 10 months, which is currently our longest follow-up.”

At the molecular level, Lo and his team found that the optimal treatment regimen involves targeting specific immune cell types—activating certain cells and decreasing the effects of others. “By knowing these immune mechanisms, we now have discrete targets to go after on top of the therapies that we already have,” says Lo. The hope is this research will facilitate enhanced immune-targeting regimens and, ultimately, improve the lives of patients with treatment resistant melanoma.

“MRA has a model of funding that’s very fast, very quick turnaround, and funds really exciting, innovative research. The Team Science approach is also very important by enabling large groups of investigators to come together to help advance the field,” says Lo.

Lo, who works in the clinic and the research lab, says it’s the excitement of discovery that keeps him going without any loss of enthusiasm. “I enjoy working at the intersection of knowledge and translatability and then taking that knowledge and making it practical. This is such rewarding and important work and MRA helps make that possible.”

Melanoma survivor and MRA Board Member Amanda Eilian.

1 Wang Y, Liu S, Yang Z, Algazi AP, Lomeli SH, Wang Y, Othus M, Hong A, Wang X, Randolph CE, Jones AM, Bosenberg MW, Byrum SD, Tackett AJ, Lopez H, Yates C, Solit DB, Ribas A, Piva M, Moriceau G, Lo RS. Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy. Cancer Cell. 2021 Aug 18:S1535-6108(21)00402-5. doi: 10.1016/j.ccell.2021.07.023. Epub ahead of print. PMID: 34416167.