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

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

SOAT1 in gallbladder cancer: Clinicopathological significance and avasimibe therapeutics

“…[74,75] By modulating the ERS signaling pathway, avasimibe plays a crucial role in tumor aggression, migration, proliferation, and death, offering a new mechanistic perspective for GBC treatment. [76,77] Avasimibe significantly reduced the proliferation, migration, and invasion abilities of GBC cells, similar to its effects in other cancer types, such as chronic myeloid leukemia and prostate cancer, where it inhibits tumor growth through various mechanisms. [78][79][80][81][82] These findings suggest that avasimibe may have broad application prospects in different types of cancer therapy.…”

“…[ 74,75 ] By modulating the ERS signaling pathway, avasimibe plays a crucial role in tumor aggression, migration, proliferation, and death, offering a new mechanistic perspective for GBC treatment. [ 76,77 ]…”

Anticancer evaluations of iodoquinazoline substituted with allyl and/or benzyl as dual inhibitors of EGFRWT and EGFRT790M: design, synthesis, ADMET and molecular docking

“…-chloroacetamido)-N-alkylbenzamide (IIIa,b), 5-iodoanthranilic acid (2), 5-iodo-N-allylanthranilic acid (3), 6-iodo-1-allylquinazoline-2,4(1H,3H)-dione (4), 5-iodo-N-benzylanthranilic acid (11), and 6-iodo-1-benzylquinazoline-2,4(1H,3H)-dione (12) were synthesized according to reported procedures. [38][39][40] 4.…”

“…Conversely, reaction of 5-iodoanthranilic acid (2) with benzyl bromide afforded the corresponding N-benzyl derivative (11). 40 Fusion of 5-iodo-N-benzylanthranilic acid (11) with urea afforded 6-iodo-1-benzylquinazoline-2,4(1H,3H)-dione (12).…”

“…Conversely, reaction of 5-iodoanthranilic acid (2) with benzyl bromide afforded the corresponding N-benzyl derivative (11). 40 Fusion of 5-iodo-N-benzylanthranilic acid (11) with urea afforded 6-iodo-1-benzylquinazoline-2,4(1H,3H)-dione (12). 40 In situ reaction of 6-iodo-1-benzylquinazoline-2,4(1H,3H)-dione (12) with chloroacetamide IIIa afforded the corresponding benzamide derivative 13.…”