A novel PI3K/mTOR dual inhibitor XH002 exhibited robust antitumor activity in NSCLC

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Non-small cell lung cancer (NSCLC) presents a significant global health challenge with high incidence and poor survival rates.
• The PI3K-Akt-mTOR (PAM) pathway is crucial for receptor tyrosine kinase (RTK) signaling and its dysregulation correlates with poor NSCLC prognosis.

Purpose of the Study:

• To evaluate the antitumor efficacy of XH002, a novel 2-amino-4-methylquinazoline derivative, as a PI3K/mTOR dual inhibitor against NSCLC.
• To investigate the mechanism of action of XH002 in repressing NSCLC cell proliferation and tumor growth.

Main Methods:

• In vitro assessment of XH002's effect on proliferation in NSCLC cells with PI3KCA mutations or high PAM pathway protein expression.
• Dose- and time-dependent analysis of XH002's impact on PAM pathway protein phosphorylation.
• In vivo studies using an EGFR-TKIs resistant NCI-H1975 xenograft model to assess tumor growth inhibition.

Main Results:

• XH002 significantly repressed proliferation in NSCLC cells with PI3KCA mutations and/or high P-S6RP, P-RAS40 expression.
• XH002 dose- and time-dependently decreased PAM pathway protein phosphorylation, inducing G1 phase cell cycle arrest.
• XH002 markedly inhibited tumor growth in an EGFR-TKIs resistant NCI-H1975 xenograft model by blocking the PAM pathway.

Conclusions:

• XH002 is a potent oral PI3K/mTOR dual inhibitor with significant antitumor efficacy.
• XH002 demonstrates excellent efficacy against PIK3CA mutant NSCLC, including cases resistant to EGFR-TKIs treatments.