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Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
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HJM-561, a Potent, Selective, and Orally Bioavailable EGFR PROTAC that Overcomes Osimertinib-Resistant EGFR Triple

Yong Du1, Yongfeng Chen1, Yuxia Wang1

  • 1Jing Medicine Technology (Shanghai) Ltd., 6th Floor, Y-building, 230 Haike Road, Shanghai, China.

Molecular Cancer Therapeutics
|May 2, 2022
PubMed

Insights

A new drug, HJM-561, effectively targets triple mutant EGFR C797S in non-small cell lung cancer (NSCLC). This orally available therapy shows promise for patients resistant to osimertinib, offering a new treatment option.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The EGFR C797S mutation is a primary resistance mechanism to osimertinib in advanced non-small cell lung cancer (NSCLC).
  • Existing treatments lack efficacy for NSCLC patients with EGFR C797S triple mutations (Del19/T790M/C797S and L858R/T790M/C797S).

Purpose of the Study:

  • To develop and evaluate an orally bioavailable EGFR PROTAC (HJM-561) for targeting EGFR C797S triple mutants.
  • To assess the efficacy of HJM-561 in preclinical models of NSCLC resistant to osimertinib.

Main Methods:

  • Synthesis and characterization of HJM-561, an orally bioavailable EGFR PROTAC.
  • In vitro assessment of HJM-561's antiproliferative activity against Ba/F3 cells harboring EGFR triple mutations and wild-type EGFR.
  • In vivo evaluation of HJM-561's antitumor activity in osimertinib-resistant Ba/F3 CDX and PDX models.

Main Results:

  • HJM-561 selectively degrades EGFR C797S-containing triple mutants.
  • HJM-561 potently inhibits proliferation of Del19/T790M/C797S and L858R/T790M/C797S Ba/F3 cells, sparing wild-type EGFR cells.
  • Oral HJM-561 demonstrated robust antitumor activity in preclinical models resistant to osimertinib.

Conclusions:

  • HJM-561 is a promising therapeutic candidate for overcoming EGFR triple mutation-mediated drug resistance in NSCLC.
  • HJM-561 offers a potential new treatment strategy for patients with advanced NSCLC harboring specific EGFR resistance mutations.

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