Fig. 7: Resensitization to paracrine signals drives gene expression and promotes drug tolerance.
From: Oncogenic EML4-ALK assemblies suppress growth factor perception and modulate drug tolerance
A Signaling through EGFR activates RAS/ERK and stimulates transcription, including of the immediate early gene EGR1. B Quantification of single-cell IF of EGR1 in STE-1 cells under the conditions indicated. C Overlay of EGR1 expression at the 6 h time point in (B). D Testing whether restored perception of paracrine signals can promote survival during ALKi treatment. E Quantification of pulses per cell in cells that died (D) or survived (S) through 22 h of imaging in the conditions where ERK pulsing could be observed. Boxplot shows median and upper/lower quartiles, whiskers show 1.5*IQR. Significance assessed by one-sided T-tests. n = 88 ALKi(D), 110 ALK(S), 136 ALKi/MMPi(D), and 46 ALKi/MMPi(S) cells. F Caspase-3 activation was assessed using the NucView reporter after 24 h treatment with the indicated drugs. Data points show proportion of 2300–3500 STE-1 cells and 3500–4500 H3122 cells. Significance assessed by one-sided T-test, n = 3 biological replicates. G, H DAPI imaging (left) and cell counts (right) of cell survival after 17 days of the indicated treatments in both H3122 (G) and STE-1 (H) cell lines. Significance assessed using one-sided T-test. n = 3 (H3122) and n = 4 (STE1) biological replicates. I Summary of the effects of drug-induced RTK resensitization.
