Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Small cell lung cancer (SCLC) subtypes, SCLC-A and SCLC-P, often overexpress BCL-2, a target for venetoclax therapy.
• However, a subset of these SCLC cell lines exhibit resistance to venetoclax, frequently associated with TP53 missense mutations conferring oncogenic, gain-of-function (Onc-p53) activities.
• Oncogenic p53 has been implicated in attenuating chemotherapeutic efficacy in SCLC.

Purpose of the Study:

• To investigate the role of Onc-p53 in venetoclax resistance in SCLC.
• To explore the synergistic potential of simultaneously targeting BCL-2 and Onc-p53 in SCLC treatment.

Main Methods:

• Genomic and drug screening platform utilizing approximately 800 solid tumor cell lines.
• Evaluation of venetoclax sensitivity in SCLC cell lines with varying BCL-2 and TP53 statuses.
• Assessment of the effects of Onc-p53 down-regulation and HSP90 inhibition (using ganetespib) on BIM expression and venetoclax sensitivity.

Main Results:

• Down-regulation of Onc-p53 increased BIM expression and sensitized SCLC-P cells to venetoclax.
• Targeting Onc-p53 with ganetespib enhanced BIM expression and sensitized both SCLC-P and SCLC-A cells to venetoclax.
• These findings suggest a mechanism where Onc-p53 contributes to venetoclax resistance.

Conclusions:

• Simultaneous targeting of BCL-2 with venetoclax and Onc-p53 with HSP90 inhibitors represents a promising therapeutic strategy for a subset of SCLC.
• This combination approach may overcome venetoclax resistance mediated by Onc-p53 in SCLC-A and SCLC-P subtypes.