A multitargeted probe-based strategy to identify signaling vulnerabilities in cancers

Area of Science:

• Cancer Biology
• Pharmacology
• Molecular Signaling

Background:

• Cancer cells rely on complex signaling networks for survival, often developing resistance to single-target drugs.
• Polypharmacology, using drugs that target multiple proteins, offers clinical advantages but is difficult to discover and validate.
• Identifying exploitable signaling vulnerabilities in cancer requires innovative strategies beyond traditional genetic approaches.

Purpose of the Study:

• To develop a non-genetic strategy for identifying cancer cell proliferation drivers and exploitable signaling vulnerabilities.
• To utilize a multitargeted kinase inhibitor (SM1-71) as a tool to discover effective polypharmacology combinations.
• To validate the approach in a KRAS-dependent non-small cell lung cancer (NSCLC) cell line.

Main Methods:

• Employed a multitargeted kinase inhibitor, SM1-71, as a tool compound.
• Utilized phenotypic screens and signaling analyses to identify target combinations.
• Applied kinase inhibitors to test the efficacy of dual inhibition strategies.

Main Results:

• Identified dual inhibition of MEK1/2 and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) as critical for blocking proliferation in H23-KRAS^G12C NSCLC cells.
• Demonstrated the effectiveness of the non-genetic strategy in discovering a specific polypharmacology combination.
• Validated the utility of SM1-71 as a tool compound for uncovering kinase dependencies.

Conclusions:

• Multitargeted tool compounds with well-defined polypharmacology are valuable for discovering kinase dependencies in cancer.
• The described non-genetic strategy is complementary to genetic approaches and generalizable to other cancer systems.
• This approach enables future mechanistic and translational studies of polypharmacology in cancer signaling vulnerabilities.