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TAS2940, a novel brain-penetrable pan-ERBB inhibitor, for tumors with HER2 and EGFR aberrations
Kei Oguchi1,2, Hikari Araki1, Shingo Tsuji1
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd, Tsukuba, Japan.
Abstract:
Genetic alterations in human epidermal growth factor receptor type 2 (HER2)/epidermal growth factor receptor (EGFR) are commonly associated with breast and lung cancers and glioblastomas. Cancers with avian erythroblastosis oncogene B (ERBB) deregulation are highly metastatic and can cause primary brain tumors. Currently, no pan-ERBB inhibitor with remarkable brain penetration is available. Here, TAS2940, a novel irreversible pan-ERBB inhibitor with improved brain penetrability, was evaluated for its efficacy against several ERBB aberrant cancer models. The selectivity of TAS2940 was evaluated by enzymatic kinase assays. The inhibitory effects of TAS2940 against ERBB genetic alterations were examined using MCF10A cells expressing various HER2 or EGFR mutations and other generic cell lines harboring deregulated ERBB expression. In vivo efficacy of TAS2940 was examined following oral treatment in subcutaneous or intracranial xenograft cancer models. TAS2940 was highly potent against cells harboring HER2/EGFR alterations. TAS2940 could selectively inhibit phosphorylation of targets and the growth of cancer cells with ERBB aberrations in vitro. TAS2940 also inhibited tumor growth in xenograft mouse models with ERBB aberrations: HER2 amplification, HER2/EGFR exon 20 insertions, and EGFR vIII mutation. TAS2940 was effective in the intracranial xenograft models of HER2/EGFR cancers and improved the survival of these mice. TAS2940 has promising therapeutic effects in preclinical study against cancers harboring HER2/EGFR mutations, especially metastatic and primary brain tumors. Our results highlight potential novel strategies against lung cancers with brain metastases harboring HER2/EGFR exon 20 insertions and glioblastomas with EGFR aberrations.
Insights
A new drug, TAS2940, shows promise as an irreversible pan-ERBB inhibitor that effectively targets cancers with human epidermal growth factor receptor type 2 (HER2)/epidermal growth factor receptor (EGFR) mutations, including brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Genetic alterations in human epidermal growth factor receptor type 2 (HER2)/epidermal growth factor receptor (EGFR) are linked to various cancers, including breast, lung, and glioblastomas.
- Cancers with avian erythroblastosis oncogene B (ERBB) deregulation are often highly metastatic and can form primary brain tumors.
- There is a clinical need for a pan-ERBB inhibitor with significant brain penetration.
Purpose of the Study:
- To evaluate the efficacy of TAS2940, a novel irreversible pan-ERBB inhibitor with enhanced brain penetrability, against ERBB-aberrant cancer models.
- To assess the selectivity and inhibitory effects of TAS2940 on cancer cells with genetic alterations in HER2/EGFR.
- To investigate the in vivo efficacy of TAS2940 in preclinical cancer models, including those with brain metastases.
Main Methods:
- Enzymatic kinase assays were used to determine the selectivity of TAS2940.
- In vitro studies involved examining the inhibitory effects of TAS2940 on cells with HER2 or EGFR mutations and deregulated ERBB expression.
- In vivo efficacy was assessed in subcutaneous and intracranial xenograft cancer models following oral administration of TAS2940.
Main Results:
- TAS2940 demonstrated high potency against cancer cells harboring HER2/EGFR alterations.
- The inhibitor selectively suppressed target phosphorylation and cancer cell growth in vitro.
- TAS2940 effectively inhibited tumor growth in xenograft models with HER2 amplification, HER2/EGFR exon 20 insertions, and EGFR vIII mutation.
- Significant efficacy was observed in intracranial xenograft models, leading to improved survival rates.
Conclusions:
- TAS2940 exhibits promising preclinical therapeutic effects against cancers with HER2/EGFR mutations, particularly brain tumors.
- The drug shows potential as a novel strategy for treating lung cancers with brain metastases and glioblastomas harboring EGFR aberrations.
- TAS2940's improved brain penetrability makes it a strong candidate for targeting central nervous system metastases.
