Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors

Abstract

Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors.DOI: http://dx.doi.org/10.7554/eLife.19671.001

Targeting autophagy in cancer

“…No devastating neurological toxicities have been observed in patients receiving these agents, suggesting that the neurodegeneration seen in mouse models after complete and irreversible inhibition of autophagy is not necessarily informative of the extent of toxicity that will occur after pharmacological treatment with autophagy inhibitors. The survival benefit associated with combining CQ with the BRAF inhibitor, vemurafenib, in brain tumor 93,116 patients provides clinical evidence that autophagy targeted therapy is a feasible clinical strategy in appropriately selected patient populations. To date, the focus of clinical trials has been on the use of lysosomal inhibition with CQ and its derivatives.…”

“…Further laboratory and clinical studies found that genetic and pharmacological autophagy inhibition could overcome multiple molecularly-distinct mechanisms of resistance to BRAF inhibition and was effective in both low and high-grade BRAF mutant brain tumors 116 . Although only a few patients with clinically-acquired resistance to the BRAF inhibitor have been treated with combinations of CQ and the BRAF inhibitor vemurafenib, it is encouraging that each person obtained clinical benefit suggesting that the autophagy inhibitor is consistently able to overcome resistance to the kinase inhibitor in patients 93,116 .…”

“…Although only a few patients with clinically-acquired resistance to the BRAF inhibitor have been treated with combinations of CQ and the BRAF inhibitor vemurafenib, it is encouraging that each person obtained clinical benefit suggesting that the autophagy inhibitor is consistently able to overcome resistance to the kinase inhibitor in patients 93,116 . Additional pre-clinical studies have shown the ability of autophagy inhibition to overcome resistance to tyrosine kinase inhibition in bladder cancer 117 , thyroid cancer 118 , NSCLC 119,120 , and ALK-positive lung cancer 121 .…”

“…2017 - Autophagy inhibition can overcome resistance to kinase inhibitors in tumour cells and in patients 116 …”

Functions of autophagy in the tumor microenvironment and cancer metastasis

“…Autophagy contributes to the therapy resistance of numerous cancers, including resistance to conventional genotoxic therapies , prostate cancer to androgen ablation therapy , breast cancer to SERMs , GIST to Imatinib , lung cancer to tyrosine kinase inhibitors , glioblastoma to temozolomide , myeloma to bortezomib , melanoma and brain cancers to B‐Raf inhibitors , as well as resistance of various cancers to PI3K inhibitors . Thus, there is a compelling rationale to combine these therapeutic approaches with agents that inhibit autophagy, such as chloroquine, an antimalarial drug that inhibits autophagy by increasing the pH of the lysosome and blocking lysosomal proteases .…”