A promiscuous kinase inhibitor reveals secrets to cancer cell survival

Abstract

Deregulated kinase signaling networks drive the growth and survival of many cancer cells. However, the genetic complexity and rapidly evolving nature of most cancer cells create challenges when identifying the most relevant kinases to inhibit to achieve optimal therapeutic benefits. A new strategy that takes advantage of a well-characterized multitargeted kinase inhibitor describes a nongenetic approach to tease out key kinases that promote proliferation of specific cancer cell types.

Figure 1.

Using polypharmacology probes to assess cancer cell line–dependent kinase signaling. Summary of proposed signaling mechanisms involved in the cell-dependent responses to the polypharmacologic probe SM1-71. Adapted from Fig. 3 by Rao et al. SM1-71–sensitive H23 cells on the left contain a KRAS^G12C mutation and are effectively inhibited by targeting IGF1R/INSR and MEK1/2. SM1-71–resistant H460 cells on the right contain KRAS^Q61K and PI3KCA^E545K mutations. The use of a PI3K inhibitor may enhance sensitivity to kinase inhibitor combinations in these cells.