Using AstraZeneca's MCL1 inhibitor to combat resistant melanoma

Investigation of protein expression (Image: AstraZeneca)
Existing melanoma treatments that involve BRAF-MEK inhibitors could be improved by adding AZD5991, an experimental AstraZeneca drug that could block a key melanoma cell survival pathway called MCL1, scientists have found. (AstraZeneca)

BRAF and MEK inhibitors—including FDA-approved combo therapies from Roche, Novartis and Pfizer’s Array BioPharma—have transformed care for melanoma. But resistance could still develop.

Researchers from the Babraham Institute, AstraZeneca and Cancer Research UK Cambridge Institute found that adding an MCL1 blocker to existing treatments could delay treatment resistance and trigger tumor cell death, according to a study published in Nature Communications.

Cancer cells rely on different signaling pathways and proteins to avoid a naturally programmed cell death process known as apoptosis. In treatment-resistant melanoma, MCL1 is a key pro-survival protein that contributes to cancer cell growth, the scientists believe.

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Many solid tumors use proteins of the BCL2 family and MCL1 to survive. After examining data from the Broad Institute’s Cancer Cell Line Encyclopedia and the National Institutes of Health’s The Cancer Genome Atlas, the Babraham-led team found that MCL1 might be the more important tumor growth driver of the two in melanoma compared to other solid tumors.

The researcher then tested an investigational MCL1 inhibitor by AstraZeneca, AZD5991, in lab dishes and patient-derived xenograft mouse models of melanoma.

AZD5991 could block MCL1, a key backup survival mechanism for melanoma cells when they are exposed to standard MEK and BRAF inhibitors, the scientists found. Combining AZD5991 with Novartis’ MEK inhibitor Mekinist or AstraZeneca and Merck’s own experimental MEK blocker selumetinib, and Roche’s BRAF inhibitor Zelboraf or Array’s BRAF inhibitor Braftovi achieved strong synergy, eliminating melanoma cells more effectively, they showed.

In mice, while AZD5991 alone couldn’t kill tumors even at high concentrations, the combos reduced the size of tumors, sometimes almost completely, and slowed their growth compared to standard treatment.

Despite the efficacy of AZD5991 in these combination studies, scientists know acquired resistance is still inevitable. So, they suggest that patients with these aggressive tumors could benefit from a different class of drug that inhibits the ERK1/2 pathway, another component that drives cancer cell growth.

In mouse models with tumors that already grew resistant to BRAF-MEK inhibition, the scientists found that combining AstraZeneca’s experimental ERK inhibitor AZ6197 with AZD5991 still led to a strong and durable tumor growth inhibition.

“This study has demonstrated that melanoma cells are addicted to the MCL1 protein for survival, but only when they are treated with the existing melanoma drugs,” the study’s lead researcher, Matthew Sale from the Babraham Institute, said in a statement. “By targeting both vulnerabilities at the same time we can kill melanoma cells, causing greater inhibition of tumor growth over a longer time period.”

AZD5591 is one of several projects a long-standing partnership between AstraZeneca and the Babraham Institute is examining. In another study recently published in Nature Communications, Sale and colleagues showed with AZ’s Array-discovered experimental MEK1/2 inhibitor selumetinib that resistance to MEK inhibition in colorectal cancer could be reversed when the drug is withdrawn.

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Besides AstraZeneca, several other teams are also working on MCL1 inhibitors. These include a collaboration between Boehringer Ingelheim and Vanderbilt University, a drug called S63845 that a team of Australian scientists found could work in multiple myeloma and Amgen’s AMG176 and AMG397, clinical trials of which in blood cancer were recently halted after a safety signal for cardiac toxicity.

For now, AZ is already testing AZD5991 with AbbVie and Roche’s BCL2 inhibitor Venclexta in blood cancers. With the current study, the team believes that the MCL1 blocker could work in tandem with existing BRAF-MEK combos in an upfront setting to stall development of melanoma treatment resistance; or, it could be paired with an ERK inhibitor to help late-stage cancers even after BRAF-MEK resistance.

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