Rescue Screens with Secreted Proteins Reveal Compensatory Potential of Receptor Tyrosine Kinases in Driving Cancer Growth

Abstract

The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 secreted proteins in cellular assays. Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative receptor tyrosine kinases (RTK). Our findings indicate a broad and versatile potential for RTKs from the HER and FGFR families as well as MET to compensate for loss of each other. We further provide evidence that combined inhibition of simultaneously active RTKs can lead to an added anticancer effect. Significance: Although initial tumor responses to kinase inhibitors can be significant, therapeutic benefit is often limited by the emergence of resistance (e.g., as a consequence of mutations in the drug target or through activation of alternative pathways to bypass dependence on the original target). Because the activation of alternative growth-promoting kinases by stimulation with their cognate ligands can constitute such a bypass mechanism, the identification of growth factors as possible mediators of resistance to kinase inhibitors is of clinical interest. Cancer Discov; 2(10); 948–59. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 857.

Genetic modifiers of EGFR dependence in non-small cell lung cancer

“…More generally, our observation that a large number of kinase inputs can redundantly sustain cancer cell survival is consistent with recent reports describing broad potential for growth factormediated inhibitor resistance in several tumor dependency models (14,15), with the finding that coactivation of multiple RTKs in glioblastoma cells overcomes reliance on any one RTK for downstream signaling activation (16), and with the identification of nine kinase-related genes whose overexpression can overcome RAF inhibition in BRAF-mutant melanoma cells (18). Taken together, our finding that a diverse set of kinases can redundantly drive the EGFR-dependent state may thus represent a more general feature of signal transduction in oncogene-dependent cancers.…”

“…Examples include amplification of the MET receptor tyrosine kinase (RTK) (9), activation of the NF-κB pathway (8), amplification of the HER2 (ERBB2) RTK (10), amplification of the CRKL gene (11), and activation of the AXL kinase (12). Notably, MET bypass can be reciprocally achieved via EGFR activation in MET-dependent cells (13), and analogous examples of reciprocal kinase switching have been reported in other kinase-driven cancer models (14,15). These and other findings suggest that compensatory kinase switching may be a more general way in which oncogene-dependent cancers overcome reliance on their primary driver kinase (14,16), but the fullrange of kinases capable of mediating EGFR bypass has not been systematically studied.…”

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

“…Yamada and colleagues ( 66 ) showed that paracrine activation by either EGFR or MET ligands from the microenvironment can trigger resistance to ALK inhibitors. Similar results were also reported in vitro by Harbinski and colleagues ( 61 ). These data suggest that the dual MET/ALK inhibitor crizotinib may be more effective than more specifi c ALK inhibitors in treating NSCLCs expressing ALK fusion proteins.…”

MET Signaling in Colon Cancer Stem-like Cells Blunts the Therapeutic Response to EGFR Inhibitors

“…13); indeed, stromal-derived growth factors can circumvent the proliferative blockade imposed by agents targeting receptor tyrosine kinases or their downstream transducers (14)(15)(16). The microenvironment could also promote therapeutic resistance at the CIC level, by providing factors that may exacerbate intrinsic drug refractoriness, and/or sustain distinctive CIC properties such as long-term self-renewal.…”