AMP-activated Protein Kinase (AMPK) activity retards growth of many types of cancers. Investigating effects of AMPK activation on breast cancer cell signaling and survival, we found that breast cancer cell lines with amplification and over-expression of HER2 or EGFR are 2- to 5-fold more sensitive to cytotoxic effects of AICAR, a canonical pharmacological activator of AMPK, than breast cancer cell lines lacking HER2 or EGFR overexpression. Paralleling effects on cell survival, AICAR leads to dose- and time-dependent inhibition of HER2 and EGFR in HER2-amplified breast cancer cells, with activation of AMPK and suppression of HER2/EGFR activity preceding commitment to cell death. Transfection of constitutively active AMPKα also leads to decreased HER2 and EGFR phosphorylation, reduced downstream signaling associated with these receptor tyrosine kinases (RTKs), and reduced breast cancer cell growth, confirming effects of AMPK activity on HER2/EGFR. Ensuing co-immunoprecipitation experiments demonstrated an interaction of HER2 with AMPK and an in vitro phosphorylation assay found that HER2 and EGFR contain sequences that are potential substrates for AMPK. Our results lead us to postulate that AMPK regulates HER2 and EGFR activity in HER2-amplified breast cancer cells and thus activation of AMPK might provide therapeutic benefit in such cancers.

Root-knot nematodes, Meloidogyne spp., are important pests of tomato (Solanum lycopersicum) and resistance to the three most prevalent species of this genus, including Meloidogyne incognita, is mediated by the Mi-1 gene. Mi-1 encodes a nucleotide binding (NB) leucine-rich repeat (LRR) resistance (R) protein. Ethylene (ET) is required for the resistance mediated by a subset of NB-LRR proteins and its role in Mi-1-mediated nematode resistance has not been characterized. Infection of tomato roots with M. incognita differentially induces ET biosynthetic genes in both compatible and incompatible interactions. Analyzing the expression of members of the ET biosynthetic gene families ACC synthase (ACS) and ACC oxidase (ACO), in both compatible and incompatible interactions, shows differences in amplitude and temporal expression of both ACS and ACO genes in these two interactions. Since ET can promote both resistance and susceptibility against microbial pathogens in tomato, we investigated the role of ET in Mi-1-mediated resistance to M. incognita using both genetic and pharmacological approaches. Impairing ET biosynthesis or perception using virus-induced gene silencing (VIGS), the ET-insensitive Never ripe (Nr) mutant, or 1-methylcyclopropene (MCP) treatment, did not attenuate Mi-1-mediated resistance to M. incognita. However, Nr plants compromised in ET perception showed enhanced susceptibility to M. incognita indicating a role for ETR3 in basal resistance to root-knot nematodes.

The AMP-activated Protein Kinase (AMPK) is a master regulator of cell metabolism, controlling fatty acid synthesis, protein synthesis and carbohydrate metabolism. Physiological states with increased AMPK activity are associated with decreased cancer incidence, leading to interest in AMPK as a potential target for cancer therapy and prevention. To explore a possible role of AMPK modulation in breast cancer therapy, we investigated how activation of AMPK affects breast cancer cell signaling and survival. Initial experiments found that breast cancer cell lines with amplification and over-expression of HER2 (BT474, HCC1419, and SKBR3) are 2-fold to 5-fold more sensitive to cytotoxic effects of AICAR, a canonical pharmacological activator of AMPK, than breast cancer cell lines that lack HER2 amplification (MCF7 and MDA231). In parallel to this activation of AMPK, we observed dose- and time-dependent inhibitory effects on phosphorylation and activity of HER2 and EGFR in these AICAR-treated, HER2-amplified breast cancer cells, with activation of AMPK and suppression of HER2/ EGFR activity preceding commitment to cell death. To further explore how AMPK activity affects HER2/ EGFR, we stably transfected HER2-amplified breast cancer cells with constitutively active AMPKα and observed that AMPK activated by this genetic manipulation also leads to decreased HER2 and EGFR phosphorylation and associated downstream signaling as well as reduced cell growth. Finally, we found that morin, a flavinoid compound previously found to inhibit fatty acid synthesis, also activates AMPK and inhibits HER2 and EGFR signaling in parallel, further supporting the link across these pathways. Our results lead us to postulate that AMPK regulates HER2 and EGFR activity in HER2-amplified breast cancer cells, and activation of AMPK might provide therapeutic benefit in such cancers. Citation Format: Teraneh Jhaveri, Ju Hyung Woo, Edward Gabrielson. AMPK regulates HER2/EGFR activity in HER2-positive breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5414. doi:10.1158/1538-7445.AM2013-5414

e19072 Background: This study aimed to provide a comprehensive overview of the evidence available on drug-induced myelosuppression in patients with MDS or AML. Methods: A systematic literature review (SLR) was conducted using MEDLINE, Embase, and Cochrane to identify studies published 2002-2022 explicitly targeting drug-induced myelosuppression with current and emerging treatments used for MDS and/or AML (venetoclax [VEN], azacitidine [AZA], magrolimab, sabatolimab, decitabine [DEC], cedazuridine, lenalidomide [LEN], low-dose cytarabine [LDAC], intensive chemotherapy [IC]) in terms of drug-induced AEs, treatment discontinuation, QOL, and MRU. Article selection was based on predefined eligibility criteria (PICO+ framework), with a focus on specific geographic regions (USA, UK, Spain, Italy, France, Germany). Results: A total of 48 studies reporting on VEN, AZA, DEC, LEN, LDAC, and IC based regimens met the inclusion criteria. In MDS populations, myelotoxicity was reported in all blood cell lineages in association with AZA, DEC, and LEN monotherapies. In AML populations, myelosuppression was reported in all blood cell lineages in association with all regimens except LEN. In general, the reported incidence of myelosuppressive AEs was higher in studies published prior to 2010 and in studies of patients with AML or MDS who had received prior treatments vs more recent studies (2018-2022) and studies of treatment-naive patients, respectively. Differences observed between the two time periods might be explained by improved supportive care (AEs prophylaxis and management). In treatment-naive AML populations, the incidence of any-grade febrile neutropenia, leukopenia, and anemia was up to 3-fold higher with AZA combination therapy vs monotherapy, and the incidence of any-grade neutropenia and febrile neutropenia was 2-fold higher with LDAC combination regimens vs monotherapy, suggestive of an additive effect. The most common reasons for treatment discontinuation were AEs and disease progression. QOL significantly improved with AZA monotherapy; however, hematologic improvement was not explicitly mentioned as the main driver. There were no data on combination therapies to indicate whether the improvement in QOL compensated for the added drug-induced AEs. The few studies that reported on the impact of myelosuppression on MRU did not provide conclusive results. Conclusions: This SLR suggests that combining ≥2 myelosuppressive drugs may result in increased toxicity; however, the lack of evidence on the impact of myelotoxicity on QOL and MRU with ≥2 myelosuppressive drugs limits informed decision-making in routine clinical practice. Further research is needed to explore the impact of drug-induced myelosuppression in patients with MDS or AML.

Background:Patients (pts) diagnosed with HR MDS are predominantly older (median age ≈70 years), with severe comorbidities and poor performance status, and often experience suboptimal outcomes with currently available therapies. In recent years, approved treatment options have remained limited; therefore, more effective therapies with tolerable safety profiles are needed to improve prognosis. This lack of evidence has prompted the evaluation of real-world evidence to understand and establish the level of baseline care and current unmet needs in pts with HR MDS.