NEW YORK – A new study published in Science Translational Medicine this week found that MEK inhibitors in combination with BET inhibitors could be potent against high MYCN-expressing triple negative breast cancer.
The authors of the study hope that their findings will accelerate development of BET inhibitors for TNBC, where there is an unmet need.
TNBC accounts for 15 percent of all breast cancer cases but is responsible for 25 percent of breast cancer-related death. There remains a lack of targeted therapies for TNBC, and more than half of patients diagnosed with the disease die within one year.
The leading treatment option for this subgroup of patients is chemotherapy, and the pathologic complete response rate is less than 30 percent when patients receive chemotherapy in the neoadjuvant setting. Patients with residual disease afterwards tend to have poor overall survival due to development of resistance and a lack of subsequent therapeutic options.
In the recently published study, researchers led by Jennifer Pietenpol and Johanna Schafer from Vanderbilt University aimed to find molecular mechanisms underlying TNBC in hopes of finding driver alterations that can be therapeutically targeted.Â
In this study, researchers evaluated the expression of the MYCN protein through immunohistochemistry in several TNBC patient cohorts, including both primary tumors and metastatic disease. They found that 45 percent to 64 percent of tumors heterogeneously express MYCN.
MYCN-expressing cells were also present in residual disease after treatment with neoadjuvant chemotherapy, as well as in TNBC cell line cultures that became resistant to PI3K inhibitors, suggesting to the team that MYCN may play a role in helping cancer cells survive treatment with chemotherapies like taxanes and anthracyclines or PI3K inhibitors.
The team generated MYCN- and MYC-expressing cell cultures with a similar genetic background and screened 158 drug compounds. Bromodomain and extra-terminal motif (BET) inhibitors effectively inhibited MYCN-expressing tumor cell growth. BET inhibitors produced little to no change in MYC levels and appear to have a stronger sensitivity for MYCN than MYC. Genetic analysis comparing MYCN-high ratio and MYC-high ratio tumors found a positive association between MYCN expression and MEK signaling. FDA-approved MEK inhibitor trametinib was one of the top hits in the team's drug screen. The drug also significantly decreased MAPK pathway signaling and MYC and MYCN expression, with a greater level of reduction in MYC signaling.
Researchers hypothesized that combining the two drugs would complementarily decrease both MYC and MYCN levels than each single agent alone, and therefore reduce tumor cell growth. In the Science Translational Medicine study, researchers demonstrated in in vitro cell cultures and patient-derived xenograft TNBC mice models that single-agent BET inhibitor and MEK inhibitor treatments decreased both MYCN and MYC expression and had a greater anti-tumor effect when used in combination. Preclinical studies have suggested BET inhibitors as a promising way to halt MYCN-driven neuronal and nonneuronal tumor cell growth.
"Both of these drugs have been under development with different safety profiles. And I think for us, what's exciting about getting this work out is for there to be some more accelerated advancement of a BET inhibitor in clinical trials," said Pietenpol in an interview.
A Phase I trial of GlaxoSmithKline's BET inhibitor GSK525762, also known as molibresib, is being studied in a variety of cancers including MYCN-driven solid tumors and has shown activity in preliminary data.Â
"MYCN is a well-recognized oncogene. It's been studied for years in neuronal tumors and has been identified as being expressed in neuroendocrine tumors or cancers. The real discovery here is finding it in a substantial percentage of triple-negative breast cancers where we really had never looked before in the field," said Pietenpol.
To evaluate MYCN expression in TNBC, the scientists identified TNBC tumors from primary and treatment-naïve cases in The Cancer Genome Atlas' (TCGA) Breast Invasive Carcinoma (BRCA) dataset. MYCN transcription was detected in 10.2 percent (20 of 197) of primary, treatment-naive cases. Elevated MYCN expression was found in a similar proportion of primary TNBC cases.
According to Pietenpol, when the researchers looked at patients with residual disease after chemotherapy or surgery, there was a slight increase in the proportion of patients expressing MYCN, about 16 percent. However, the team did not find higher expression of MYCN in TNBC tumors that have metastasized to the brain.
When TNBC PDX models were subjected to single-agent BET inhibitor treatment, researchers observed the greatest tumor growth inhibition in models with high MYCN expression. MYCN-high models had a 63 percent tumor growth inhibition with Incyte's BET inhibitor INCB054329 compared to 40 percent in MYCN-intermediate models and 38 percent in MYCN-low models.
When treated with Roche's BET inhibitor JQ1, MYCN-high models had 83 percent tumor growth inhibition, MYCN-intermediate models had 75 percent tumor growth inhibition, and MYCN-low models had 57 percent tumor growth inhibition. Combining BET inhibitors with MEK inhibitor trametinib resulted in significant reduction in tumor volume in MYCN-high and MYCN-intermediate expression models.
"We propose the clinical development of combination BET inhibitor and MEK inhibitor for patients with advanced TNBC, with parallel evaluation of MYCN as a potential marker for patient selection," the authors concluded.