Autophagy inhibition may help overcome BRAF inhibitor resistance in melanoma

Among melanoma patients treated with either BRAF inhibitors or a combination of BRAF and MEK inhibitors, those with higher rates of drug-related autophagy appear to have significantly lower response rates and shorter PFS, according to study results.

“Elevated levels of autophagy in primary tumors correlated with proliferation and lymph node metastases in human melanoma tumors,” the researchers wrote. “These results demonstrate that autophagy levels can be high before treatment in melanoma, but may be induced even further during therapies, and support the notion that autophagy modulation may be especially effective as a therapeutic strategy in melanoma.”

In the study, researchers evaluated paired biopsy samples from 15 patients with BRAF-mutant melanoma treated with BRAF inhibitors. They stained the samples for LC3B, a known marker for autophagy.

Study participants received one of three treatment regimens: 10 patients underwent single-agent treatment with the BRAFinhibitor vemurafenib (Zelboraf, Genentech), two were treated with the BRAF inhibitor dabrafenib (Taflinar, GlaxoSmithKline), and three were treated with a combination of dabrafenib and the MEK inhibitor trametinib (Mekinist, GlaxoSmithKline).

The researchers evaluated the tumor biopsies using the LC3B immunohistochemistry (IHC) assay before treatment, and subsequently tested tumors that demonstrated regrowth and resistance to the BRAF inhibitor treatment. The LC3B IHC for pre-therapy vs. tumor regrowth samples were 13% vs. 7% for 1+, 67% vs. 7% (P<.05) for 2+, 20% vs. 40% (P<.05) for 3+, and 0% vs. 46% (P<.05) for 4+.

In 74% of the cases, the pretreatment biopsy samples had lower LC3B scores than in the resistance cases. Pretreatment and resistance samples had equal LC3B scores in 13% of cases, and the pretreatment samples had higher LC3B scores than resistance samples in 13% of cases.

In a separate analysis, the researchers acquired tumor biopsies from two patients with BRAF mutant melanoma who were participating in clinical trials of vemurafenib.

The researchers observed that cells that survived the stress of BRAF inhibition 15 days after treatment initiation had a two- to sixfold increase in autophagic vesicles compared with baseline. Tumor biopsies at the time of progression showed elevated levels of autophagy in both participants.

The researchers also analyzed changes in LC3B levels in samples showing progression with clinical outcomes from BRAF inhibition treatment. They found there was a 17% confirmed partial response rate (>30% tumor reduction compared with baseline on two CT scans) in patients who demonstrated a 2+ increase in LC3B staining at progression, whereas those who did not have a 2+ increase in LC3B staining in progression compared with baseline had an 88% confirmed partial response rate.

Consistent with this finding, patients whose biopsies had 4+ increases in LC3B staining at progression had significantly shorter PFS (median, 229 days) than patients with lower levels of LC3B staining in progression samples (median, 275 days).

 

Ravi K. Amaravadi

The researchers found that BRAF inhibition or BRAF/MEK inhibition treatment triggered cytoprotective autophagy, and autophagy inhibition was useful in optimizing BRAF inhibition-induced apoptosis and antitumor activity.

“As the use of BRAF inhibitors become more widespread, we’ll need to discover new options for our patients so they can overcome this destined resistance,” Ravi K. Amaravadi, MD, assistant professor of medicine in the division of hematology/oncology at the Perelman School of Medicine in Philadelphia, said in a press release. “Here, we have a new pathway that links the BRAF mutation to endoplasmic reticulum stress and autophagy that could be exploited with an already-approved FDA drug, which I believe could be a game changer for this group of patients.”

Disclosure: Amaravadi and another researcher are co-inventors of a licensed patent, which has generated no revenue, protecting the structure and use of Lys05 and derivatives.