Combining Autophagy Inhibition With Dabrafenib May Provide Benefit for Melanoma Patients

The removal of a gene involved in the cellular self-cannibalization process of autophagy could provide therapeutic benefit to patients with melanoma.

The removal of a gene involved in the cellular self-cannibalization process of autophagy could provide therapeutic benefit to patients with melanoma. Investigators at Rutgers Cancer Institute of New Jersey now have demonstrated autophagy inhibition may be of therapeutic value by augmenting the antitumor activity of BRAF inhibitors.

Treatment with the BRAF inhibitor dabrafenib (Tafinlar) appears to decrease tumor growth and induce senescence, and may be more pronounced in tumors with ATG7 deficiency. The researchers report in the current online edition of Cancer Discovery that ATG7 may promote melanoma by limiting oxidative stress and overcoming senescence.   

Senior author Janice Mehnert, MD, who is a medical oncologist in the Melanoma and Soft Tissue Oncology Program at the Cancer Institute of New Jersey, said the discovery that ATG7 promotes the growth of melanoma tumors suggests that the development of agents targeting autophagy may effectively inhibit melanoma growth. Autophagy is a process in which intracellular components are recycled in order to help sustain cell growth.

Dr. Mehnert said clinical trials seeking to block the process of autophagy are ongoing at Rutgers Cancer Institute. So far, she and her colleagues have found that the essential autophagy gene ATG7 promotes development of BRAF V600E-mutant, PTEN-null melanomas. ATG7 does this by overcoming senescence. Subsequently, deleting ATG7 appears to facilitate senescence induction and antitumor activity of BRAF inhibition.

Half of all melanomas harbor an activating mutation in the BRAF gene that turns on the MAP kinase pathway. Activation of the MAP kinase pathway promotes tumor growth and survival. Drugs designed to selectively block activated BRAF have led to significant improvement in clinical response and overall survival in melanoma patients. However, resistance to these drugs often develops and leads to recurrence.

Investigators tested the consequence of removing the autophagy gene known as ATG7 from laboratory models of BRAF-driven melanoma. The research team utilized a genetically engineered mouse model of melanoma driven by oncogenic BRAF V600E, and deficiency in the PTEN tumor suppressor gene in melanocytes to test the functional consequences of loss of the essential autophagy gene ATG7.

The researchers found that ATG7 deficiency prevented melanoma development by BRAF V600E and allelic PTEN loss. This suggests that autophagy is essential for melanomagenesis. In this investigation, Dr. Mehnert and her team found that BRAF V600E-mutant, PTEN-null, ATG7-deficient melanomas displayed accumulation of autophagy substrates and growth defects. These changes lead to extended animal survival. The researchers report that ATG7-deleted tumors showed increased oxidative stress and senescence. The study found that treatment with the BRAF inhibitor dabrafenib decreased tumor growth and induced senescence that was more pronounced in tumors with ATG7 deficiency.