Abstract
Melanoma patients harboring the BRAFV600E mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH), overcomes resistance of BRAFV600E melanoma cells to vemurafenib, leading to tumor elimination in corresponding human xenograft models in mice. We report the synthesis of PAH and demonstrate that this compound inhibits the drug efflux activity of the Hedgehog receptor, Patched. Our SAR study allowed identifying a key pharmacophore responsible for this activity. We showed that Patched is strongly expressed in metastatic samples from a cohort of melanoma patients and is correlated with decreased overall survival. Patched is a multidrug transporter that uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that PAH is a highly promising lead for the treatment of vemurafenib resistant BRAFV600E melanoma.
Highlights
One of the major challenges in the clinical management of cancer is resistance to chemotherapeutics.Multidrug resistance (MDR) has been intensively studied, and overexpression of ATP-binding cassette (ABC) transporters has been considered to be the most prominent underlying mechanism for MDR.Cancers 2020, 12, 1500; doi:10.3390/cancers12061500 www.mdpi.com/journal/cancersDespite research efforts to develop compounds that inhibit the efflux activity of ABC transporters and increase classical chemotherapy efficacy, to date, the Food and Drug Administration has not approved the use of any ABC transporter inhibitor due to toxicity issues [1]
Normalized gene expression data and matching clinical information for cutaneous melanoma tumors were downloaded from The Cancer Genome Atlas (TCGA), separated into primary tumor samples (n = 103) and metastatic tumor samples (n = 368)
We report that Ptch1 is strongly expressed in primary and metastatic specimens from a cohort of 471 cutaneous melanoma patients from The Cancer Genome Atlas (TCGA), and that a high expression level of Ptch1 in patient-derived metastatic samples significantly correlated with a lower overall survival time (Figure 1A)
Summary
One of the major challenges in the clinical management of cancer is resistance to chemotherapeutics. Despite research efforts to develop compounds that inhibit the efflux activity of ABC transporters and increase classical chemotherapy efficacy, to date, the Food and Drug Administration has not approved the use of any ABC transporter inhibitor due to toxicity issues [1]. The Hedgehog (Hh) signaling pathway controls cell differentiation and proliferation. It plays a crucial role during embryonic development and, in adulthood, it is involved in stem cell homeostasis and tissue regeneration. Hh signaling is involved in cancer development, progression, and metastasis. Aberrant activation of Hh signaling has been observed in many aggressive cancers [2], in particular, in cells exhibiting resistance to chemotherapy such as cancer stem cells or tumor-initiating cells [3]. The Hh receptor, Patched (Ptch1), whose expression is induced upon activation of the
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