Recombinant T. maccoyii Insulin-like growth factor 1 receptor

Most cancer cells are dependent on a network of deregulated signaling pathways for survival and are insensitive, or rapidly evolve resistance, to selective inhibitors aimed at a single target. For these reasons, drugs that target more than one protein (polypharmacology) can be clinically advantageous. The discovery of useful polypharmacology remains serendipitous and is challenging to characterize and validate. In this study, we developed a non-genetic strategy for the identification of pathways that drive cancer cell proliferation and represent exploitable signaling vulnerabilities. Our approach is based on using a multitargeted kinase inhibitor, SM1-71, as a tool compound to identify combinations of targets whose simultaneous inhibition elicits a potent cytotoxic effect. As a proof of concept, we applied this approach to a KRAS-dependent non-small cell lung cancer (NSCLC) cell line, H23-KRAS(G12C). Using a combination of phenotypic screens, signaling analyses, and kinase inhibitors, we found that dual inhibition of MEK1/2 and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) is critical for blocking proliferation in cells. Our work supports the value of multitargeted tool compounds with well-validated polypharmacology and target space as tools to discover kinase dependences in cancer. We propose that the strategy described here is complementary to existing genetics-based approaches, generalizable to other systems, and enabling for future mechanistic and translational studies of polypharmacology in the context of signaling vulnerabilities in cancers.

Multidrug resistance (MDR) is still a major reason for therapeutic failure in cancers. The mechanisms underlying MDR are multifactorial and are not fully understood. miRNAs are evolutionarily conserved non-coding RNAs that function as key post-transcriptional regulators of gene expression. Emerging evidence indicates a vital role of miRNAs in the resistance to cancer treatments and suggests their potential for cancer therapy, as they can modulate multiple mechanisms link to the development of MDR. This review summarizes the recent findings on the role of miRNAs in MDR, and highlights the molecular targets and mechanisms of miRNA regulated pathways in MDR. Finally, the challenges and prospects of miRNA-targeted therapies for reversing drug resistance are reviewed.