MUC1-C dependence in treatment-resistant prostate cancer uncovers a target for antibody-drug conjugate therapy
Keisuke Shigeta, Tatsuaki Daimon, Hiroshi Hongo, Sheng-Yu Ku, Hiroki Ozawa, Naoki Haratake, Atsushi Fushimi, Ayako Nakashoji, Atrayee Bhattacharya, Shinkichi Takamori, Michihisa Kono, Masahiro Rokugo, Yuto Baba, Takeo Kosaka, Mototsugu Oya, Justine Jacobi, Mark D. Long, Himisha Beltran, Donald Kufe
Keisuke Shigeta, Tatsuaki Daimon, Hiroshi Hongo, Sheng-Yu Ku, Hiroki Ozawa, Naoki Haratake, Atsushi Fushimi, Ayako Nakashoji, Atrayee Bhattacharya, Shinkichi Takamori, Michihisa Kono, Masahiro Rokugo, Yuto Baba, Takeo Kosaka, Mototsugu Oya, Justine Jacobi, Mark D. Long, Himisha Beltran, Donald Kufe
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Research Article Oncology Therapeutics

MUC1-C dependence in treatment-resistant prostate cancer uncovers a target for antibody-drug conjugate therapy

Abstract

Androgen receptor–positive prostate cancer (PC), castration-resistant prostate cancer (CRPC), and neuroendocrine prostate cancer (NEPC) invariably become resistant to treatment with targeted and cytotoxic agents. Multiple pathways have been identified as being responsible for these pleiotropic mechanisms of resistance. The mucin 1 (MUC1) gene is aberrantly expressed in CRPC/NEPC in association with poor clinical outcomes; however, it is not known if the oncogenic MUC1-C/M1C protein drives treatment resistance. We demonstrated that MUC1-C is necessary for resistance of (i) PC cells to enzalutamide (ENZ) and (ii) CRPC and NEPC cells to docetaxel (DTX). Our results showed that MUC1-C–mediated resistance is conferred by upregulation of aerobic glycolysis and suppression of reactive oxygen species necessary for self-renewal. Dependence of these resistant phenotypes on MUC1-C for the cancer stem cell (CSC) state identified a potential target for treatment. In this regard, we further demonstrated that targeting MUC1-C with an M1C antibody-drug conjugate (ADC) is highly effective in suppressing (i) self-renewal of drug-resistant CRPC/NEPC CSCs and (ii) growth of treatment-emergent NEPC tumor xenografts derived from drug-resistant cells and a patient with refractory disease. These findings uncovered a common MUC1-C–dependent pathway in treatment-resistant CRPC/NEPC progression and identified MUC1-C as a target for their therapy with an M1C ADC.

Authors

Keisuke Shigeta, Tatsuaki Daimon, Hiroshi Hongo, Sheng-Yu Ku, Hiroki Ozawa, Naoki Haratake, Atsushi Fushimi, Ayako Nakashoji, Atrayee Bhattacharya, Shinkichi Takamori, Michihisa Kono, Masahiro Rokugo, Yuto Baba, Takeo Kosaka, Mototsugu Oya, Justine Jacobi, Mark D. Long, Himisha Beltran, Donald Kufe

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Figure 7

Targeting MUC1-C with an ADC is effective against t-NEPC cells growing in vitro and as tumor xenografts.

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Targeting MUC1-C with an ADC is effective against t-NEPC cells growing i...
(A) Cells were analyzed for the indicated transcripts by qRT-PCR. The results (mean ± SD of 4 determinations) are expressed as relative levels compared with that obtained for H660 cells (assigned a value of 1) (t test; n = 3). (B) Immunoblot analysis of chromatin from H660, WCM154, and WCM155 cells run at different times. (C) Cells were analyzed by flow cytometry with a control IgG and MAb-3D1. Shown are histograms and percentage of positive for MUC1-C expression (left). The bar plot depicts MFI fold-change (MAb-3D1/IgG). The results (mean ± SD of 3 determinations) are expressed as relative levels compared with that obtained for 3D1-negative control cells (assigned a value of 1) (right). (D) Cells treated with PBS or M1C ADC for 7 days were analyzed for cell viability. (E) Cells treated with 50 nM M1C ADC for 7 days were analyzed for tumorsphere formation (t test; n = 3). (F) Treatment schedule for NSG mice with 100 mm3 H660 tumors. (G) Tumor volumes (mean ± SD) on day 42 were 1,810.9 ± 467.0 mm3 in the PBS group and 47.5 ± 41.3 mm3 in the M1C ADC group (P value = 0.001). (H) Percentage change in volume from baseline shown as a waterfall plot. (I) Treatment schedule for NOD/SCID-γ mice with 100 mm3 WCM154 patient-derived xenograft (PDX) tumors. (J) Tumor volumes (mean ± SD) for 6 mice on day 44 were 1,152.6 ± 384.9 mm3 in the PBS control group and 28.4 ± 32.2 mm3 in the M1C ADC group (P value = 0.018). (K) Percentage change in volume for each WCM154 tumor from baseline shown as a waterfall plot. Scale bar, 100 μm. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.