Autophagy Inhibition in BRAF-Driven Skin Cancers Raises Hopes, Questions

The addition of autophagy inhibitors to BRAF-targeted therapy may be a meaningful solution to therapeutic resistance among patients with BRAF-mutated cancers, but a new review article cautions that more evidence is needed to better understand when and why the strategy could work.

Co-authors Mona Foth, PhD, and Martin McMahon, PhD, both of the Huntsman Cancer Institute, Salt Lake City, Utah, noted that the 6 BRAF has been implicated in a number of cancer types, and the FDA has already approved pharmacological inhibition of BRAF and its direct effector MEK1/2 for cancers including melanoma, non–small cell lung carcinoma, and thyroid cancer.

“However, despite the success of this vertical inhibition strategy, the durability of patient responses is often limited by the phenomenon of primary or acquired drug resistance,” they wrote.

Autophagy, the process of cellular recycling, has been linked to tumor progression and is believed to provide protection to cancer cells during chemotherapy.

“To this end, BRAF inhibitor (BRAFi)-resistant cells often display increased autophagy compared to responsive lines,” the authors wrote. “Several mechanisms have been proposed for BRAFi-induced autophagy, such as activation of the endoplasmic reticulum (ER) stress gatekeeper GRP78, AMP-activated protein kinase, and transcriptional regulation of the autophagy regulating transcription factors TFEB and TFE3 via ERK1/2 or mTOR inhibition.”

In their review, published in Cancers, Foth and McMahon review some of the latest evidence related to these strategies.

In some areas, the incorporation of autophagy inhibition has created optimism. For instance, combined inhibition of AKT (protein kinase B) and autophagy reduced the metabolic activity of metastatic melanoma cells in culture, the authors said. Yet, inhibition of autophagy does not appear to be a complete solution, either as monotherapy or when combined with standard chemotherapy, they wrote. If autophagy inhibition is found to work well with therapies like BRAF inhibitors, the investigators said there is also evidence that restricting dietary intake of certain essential nutrients, such as leucine, can enhance outcomes.

When it comes to patients who are already resistant to BRAF inhibitors, the authors said emerging research supports the idea that autophagy inhibition might help resensitize resistant tumors.

Yet, despite the positive signs, they also said it can be difficult to extract clear conclusions from the existing data due to the biological complexity of autophagy regulation and the context-dependent nature of the findings that have been reported.

“Moreover, conclusions regarding the regulation of autophagy by cancer-driving oncoproteins may be confounded by the accumulation of additional genetic alterations over time that promote cancer progression,” they said.

Although combined inhibition of oncogenic signaling plus autophagy appears to be an effective strategy in some cancers, the authors noted that some of the existing scholarship has relied on 4-amino-quinolones like chloroquine, which “have pleiotropic effects on cancer cell physiology and are not on specific and selective inhibitors of autophagy.”

Thus, Foth and McMahon noted, “Since autophagy has been shown to play a tumor-suppressive role in a cancer stage-, tissue-, and/or context-dependent manner, caution must be exercised in the broader clinical deployment of this therapeutic strategy.”

Reference

Foth M, McMahon M. Autophagy inhibition in BRAF-driven cancers. Cancers (Basel). Published online July 13, 2021. doi:10.3390/cancers13143498