Anti-cancer effect of afatinib, dual inhibitor of HER2 and EGFR, on novel mutation HER2 E401G in models of patient-derived cancer

• Published in: BMC cancer Vol. 23; no. 1; pp. 77 - 11
• Main Authors: Harada, Yohei, Sato, Akemi, Nakamura, Hideaki, Kai, Keita, Kitamura, Sho, Nakamura, Tomomi, Kurihara, Yuki, Ikeda, Sadakatsu, Sueoka, Eisaburo, Kimura, Shinya, Sueoka-Aragane, Naoko
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 23.01.2023; BioMed Central; BMC
• Subjects: Afatinib; Analysis; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Cancer; Cancer patients; Care and treatment; Cell Line, Tumor; Copy number; Drugs; EGFR; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB-2 protein; Experiments; Extracellular domain; Genetic aspects; Health aspects; HER2; Humans; Kinases; Laboratory animals; Lapatinib; Mutation; Neoplasms - drug therapy; Next-generation sequencing; Patient-derived cancer model; Patients; Physical characteristics; Precision medicine; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Receptor, ErbB-2 - metabolism; Review boards; Statistical analysis; Trastuzumab; Tumors; Tyrosine; Xenografts; Japan; Denmark; United States > US; Patient-derived cancer model; Afatinib; HER2; EGFR; Extracellular domain
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-022-10428-3

Precision medicine with gene panel testing based on next-generation sequencing for patients with cancer is being used increasingly in clinical practice. HER2, which encodes the human epidermal growth factor receptor 2 (HER2), is a potentially important driver gene. However, therapeutic strategies aimed at mutations in the HER2 extracellular domain have not been clarified. We therefore investigated the effect of EGFR co-targeted therapy with HER2 on patient-derived cancer models with the HER2 extracellular domain mutation E401G, based on our previous findings that this mutation has an epidermal growth factor receptor (EGFR)-mediated activation mechanism. We generated a xenograft (PDX) and a cancer tissue-originated spheroid (CTOS) from a patient's cancer containing an amplified HER2 E401G mutation. With these platforms, we compared the efficacy of afatinib, a tyrosine kinase inhibitor having anti-HER2 and anti-EGFR activity, with two other therapeutic options: lapatinib, which has similar properties but weaker EGFR inhibition, and trastuzumab plus pertuzumab, for which evidence exists of treatment efficacy against cancers with wild-type HER2 amplification. Similar experiments were also performed with H2170, a cell line with wild-type HER2 amplification, to contrast the characteristics of these drug's efficacies against HER2 E401G. We confirmed that PDX and CTOS retained morphological and immunohistochemical characteristics and HER2 gene profiles of the original tumor. In both PDX and CTOS, afatinib reduced tumor size more than lapatinib or trastuzumab plus pertuzumab. In addition, afatinib treatment resulted in a statistically significant reduction in HER2 copy number at the end of treatment. On the other hand, in H2170 xenografts with wild-type HER2 amplification, trastuzumab plus pertuzumab was most effective. Afatinib, a dual inhibitor of HER2 and EGFR, showed a promising effect on cancers with amplified HER2 E401G, which have an EGFR-mediated activation mechanism. Analysis of the activation mechanisms of mutations and development of therapeutic strategies based on those mechanisms are critical in precision medicine for cancer patients.