Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic cancer pathophysiology, promoting cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to unravel mechanisms of resistance to IGF-1R inhibition in pancreatic cancer and develop novel strategies to improve the activity of standard-of-care therapies. Growth factor screening in pancreatic cancer cell lines was performed to identify activators of prosurvival PI3K/AKT signaling. The prevalence of activating growth factors and their receptors was assessed in pancreatic cancer patient samples. Effects of a bispecific IGF-1R and ErbB3 targeting antibody on receptor expression, signaling, cancer cell viability and apoptosis, spheroid growth, and chemotherapy activity in pancreatic cancer xenograft models were determined. Growth factor screening in pancreatic cancer cells revealed insulin-like growth factor 1 (IGF-1) and heregulin (HRG) as the most potent AKT activators. Both growth factors reduced pancreatic cancer cell sensitivity to gemcitabine or paclitaxel in spheroid growth assays. Istiratumab (MM-141), a novel bispecific antibody that blocks IGF-1R and ErbB3, restored the activity of paclitaxel and gemcitabine in the presence of IGF-1 and HRG Dual IGF-1R/ErbB3 blocking enhanced chemosensitivity through inhibition of AKT phosphorylation and promotion of IGF-1R and ErbB3 degradation. Addition of istiratumab to gemcitabine and nab-paclitaxel improved chemotherapy activity Our findings suggest a critical role for the HRG/ErbB3 axis and support the clinical exploration of dual IGF-1R/ErbB3 blocking in pancreatic cancer. .

Androgen exposure stimulates the growth of beard hair follicles. The follicle dermal papilla appears to be the site of androgen action; however, the molecular mechanisms that regulate this process are not well understood. In an attempt to identify genes that contribute to the androgen-responsive phenotype, we compared gene expression patterns in unstimulated and androgen-treated cultured human dermal papilla cells isolated from beard (androgen-sensitive) and occipital scalp (androgen-insensitive) hair follicles. Through this analysis, we identified three genes that are expressed at significantly higher levels in beard dermal papilla cells. One of these genes, sfrp-2 has been identified as a dermal papilla signature gene in mouse pelage follicles. Two of these genes, mn1 and atp1beta1, have not been studied in the hair follicle. A fourth, fibulin-1d, was slightly upregulated in beard dermal papilla cells. The differences in the expression of these genes in cultured beard and scalp dermal papilla cells reflected similar differences in microdissected dermal papilla isolated from intact beard and scalp follicles. Our findings introduce potentially novel signaling pathways in dermal papilla cells. In addition, this study supports that cultured dermal papilla cells provide a cell-based model system that is reflective of the biology of in vivo hair follicle cells.

Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by highaffinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor-antagonist interactions. Model simulations suggested that an oligoclonal antibody combination may overcome signal amplification within the EGFR:ERK pathway driven by all EGFR ligands. Based on this, we designed MM-151, a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, nonoverlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to an approximately 65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated antiproliferative activity against high-affinity EGFR ligands, either singly or in combination, while cetuximab activity was largely abrogated under these conditions. We confirmed this finding both in vitro and in vivo in a cell line model of autocrine high-affinity ligand expression. Together, these preclinical studies provide rationale for the clinical study of MM-151 and suggest that high-affinity EGFR ligand expression may be a predictive response marker that distinguishes MM-151 from other anti-EGFR therapeutics.

are employees and shareholders of Deciphera Pharmaceuticals. D.L.F. is founder of Deciphera Pharmaceuticals and a member of its scientific advisory board. S.C.W. is a former employee of Deciphera Pharmaceuticals. B.W. and L.D. are investigators on the clinical study of vimseltinib. B.W. has received financial or material support from GlaxoSmithKline, Lilly, Adaptimmune, Advenchen Laboratories, Daiichi Sankyo, Deciphera, Agenus, and Novartis. B.W. is a paid consultant for Deciphera, Adaptimmune, Springworks, Immune Design, and Daiichi Sankyo and has received research support from Merck Sharp & Dohme, and Agenus. L.D. has received research support from Novartis, Eisai, and BTG. L.D. is a paid consultant for Daiichi Sankyo and Epizyme. Deciphera Pharmaceuticals has patents on vimseltinib.

Therapeutically targeting receptor tyrosine kinases has proven to be paramount to overcoming chemotherapy resistance in several cancer indications, improving patient outcomes. Insulin-Like Growth Factor Receptor 1 (IGF-1R) and Epidermal Growth Factor Receptor 3 (ErbB3) have been implicated as two such drivers of resistance, however their simultaneous role in ovarian cancer chemotherapy resistance remains poorly elucidated. The aim of this work is to determine the effects of dual IGF-1R/ErbB3 inhibition on ovarian cancer cell signaling, growth, and in vivo efficacy. Assessment of in vitro chemotherapy response across a panel of ovarian cancer cell lines revealed that increased IGF-1R cell surface expression correlates with decreased sensitivity to chemotherapy, and that growth induced by IGF-1R and ErbB3 ligands is blocked by the tetravalent bispecific antibody targeting IGF-1R and ErbB3, istiratumab. In vitro chemotherapy treatment increased ovarian cancer cell line capacity to activate prosurvival PI3K signaling in response to ligand, which could be prevented with istiratumab treatment. Furthermore, in vivo efficacy of standard of care chemotherapies using a xenograft model of ovarian cancer was potentiated with istiratumab. Our results suggest a role for IGF-1R and ErbB3 in driving chemotherapy resistance of ovarian cancer.