Loss of MIG-6 results in endometrial progesterone resistance via ERBB2

Female subfertility is highly associated with endometriosis. Although the exact etiology of endometriosis-related infertility remains to be determined, endometrial progesterone resistance has recently been suggested as a crucial element in the development of endometrial diseases. Here, we report that MIG-6, a progesterone-induced gene, is downregulated in the endometrium of infertile women with endometriosis and in a non-human primate model of endometriosis. In an endometriosis mouse model with a fluorescent reporter used to identify lesions, an increase of endometriosis development and implantation failure were observed in mice with Mig-6 deficient endometrium compared to controls. MIG-6 is known to inhibit ERBB2, which we found overexpressed in the endometrium from uterine-specific Mig-6 knock-out mice (Pgrcre/+Mig-6f/f; Mig-6d/d). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduced Erbb2 ablation in Mig-6d/d mice (Mig-6d/dErbb2d/d mice). The additional knockout of Erbb2 rescued all phenotypes seen in Mig-6d/d mice including endometrial progesterone resistance, infertility, and endometriosis lesion development. Transcriptomic analysis showed that genes differentially expressed in Mig-6d/d mice reverted to their normal expression amounts in Mig-6d/dErbb2d/d mice. Together, our results demonstrate that MIG-6-induced ERBB2 overexpression causes endometrial progesterone resistance and a nonreceptive endometrium in endometriosis-related infertility and that ERBB2 targeting reverses these effects.

Pertuzumab plus trastuzumab (P+T) in patients (Pts) with colorectal cancer (CRC) with ERBB2 amplification or overexpression: Results from the TAPUR Study.

132 Background: TAPUR is a phase II basket trial evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with ERBB2 overexpression or amplification treated with P+T are reported. Methods: Eligible pts had advanced CRC, no standard treatment (tx) options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts had ERBB2 overexpression or amplification, or certain ERBB2 mutations. Recommended dosing after initial dosing was P, 420 mg IV over 30-60 mins every 3 weeks (wks) and T, 6 mg/kg over 30-60 mins every 3 wks. Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16+ wks per RECIST (SD16+)), 18 more pts enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight pts enrolled from November 2016 to September 2018 were evaluable for efficacy and safety. Demographics and outcomes are summarized in Table. All pts had ERBB2 amplification; 1 also had an ERBB2 mutation. 79% of pts had at least 3 prior txs. Four PR and 10 SD16+ were observed for DC and OR rates of 50% (90% CI, 36% to 60%) and 14% (95% CI, 4% to 33%), respectively. Two pts had at least one grade 3 AE or SAE at least possibly related to P+T including anemia, infusion reaction, and left ventricular dysfunction. Conclusions: The combination of P+T showed anti-tumor activity in heavily pre-treated CRC pts with ERBB2 amplification . Additional analyses by RAS mutation status are pending. Further study is warranted to confirm efficacy of P+T in this population. Clinical trial information: NCT02693535. [Table: see text]

Stiffness of the microenvironment upregulates ERBB2 expression in 3D cultures of MCF10A within the range of mammographic density

The effects of the stiffness of the microenvironment on the molecular response of 3D colony organization, at the maximum level of mammographic density (MD), are investigated. Phenotypic profiling reveals that 3D colony formation is heterogeneous and increased stiffness of the microenvironment, within the range of the MD, correlates with the increased frequency of aberrant 3D colony formation. Further integrative analysis of the genome-wide transcriptome and phenotypic profiling hypothesizes overexpression of ERBB2 in the premalignant MCF10A cell lines at a stiffness value that corresponds to the collagen component at high mammographic density. Subsequently, ERBB2 overexpression has been validated in the same cell line. Similar experiments with a more genetically stable cell line of 184A1 also revealed an increased frequency of aberrant colony formation with the increased stiffness; however, 184A1 did not demonstrate overexpression of ERBB2 at the same stiffness value of the high MD. These results suggest that stiffness exacerbates premalignant cell line of MCF10A.