A combinatorial strategy for treating KRAS-mutant lung cancer

Abstract

Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proven difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying combination targets for trametinib, an FDA-approved MEK inhibitor that acts downstream of KRAS to suppress signaling through the mitogen-activated protein kinase (MAPK) cascade. Informed by a short-hairpin RNA (shRNA) screen, we show that trametinib provokes a compensatory response involving the fibroblast growth factor receptor 1 (FGFR1) that leads to signaling rebound and adaptive drug resistance. As a consequence, genetic or pharmacologic inhibition of FGFR1 in combination with trametinib enhances tumor cell death in vitro and in vivo. This compensatory response shows distinct specificities – it is dominated by FGFR1 in KRAS mutant lung and pancreatic cancer cells, but is not activated or involves other mechanisms in KRAS wild-type lung and KRAS-mutant colon cancer cells. Importantly, KRAS-mutant lung cancer cells and patient tumors treated with trametinib show an increase in FRS2 phosphorylation, a biomarker of FGFR activation; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations. These results demonstrate that FGFR1 can mediate adaptive resistance to trametinib and validate a combinatorial approach for treating KRAS-mutant lung cancer.

Vemurafenib-resistant BRAF-V600E-mutated melanoma is regressed by MEK-targeting drug trametinib, but not cobimetinib in a patient-derived orthotopic xenograft (PDOX) mouse model

“…TRA was shown to affect the fibroblast growth factor receptor 1 (FGFR1) leading to drug resistance [32]. In a recent study, inhibition of FGFR1 in combination with TRA enhanced cancer cell death in vitro and in vivo [32].…”

Synthetic Lethal Vulnerabilities in KRAS-Mutant Cancers

“…These studies have also shown that KRAS mutant cells harbor increased dependence on RTK signaling pathways, as small molecule inhibitors of IGF1R and MET exhibit some preferential selectivity for subsets of KRAS mutant lines over KRAS wild-type lines (Ebi et al 2011; Molina-Arcas et al 2013). In addition, MAPK inhibition leads to increased dependence on RTK signaling, with combined targeting of MEK1/2 and IGF1R (Ebi et al 2011; Molina-Arcas et al 2013) or FGFR1 (Manchado et al 2016) demonstrating enhanced differential impact on KRAS mutant cells over wild-type cells. Moreover, KRAS-MAPK effector signaling ultimately leads to activation of AP-1 transcription factors and upregulation of cell cycle regulatory proteins, such as cyclin D1 ( CCND1 ) which promotes G1/S cell cycle progression.…”

“…Lastly, since most treatment strategies in KRAS mutant cancers will require combination therapies, functional genetic screening in the context of small molecule inhibition of key KRAS effector signaling pathways may prove most fruitful for the identification of high-priority KRAS synthetic lethal interactions. A number of screens have been performed using RNAi technologies to identify combination therapy targets with MAPK pathway inhibition, including FGFR1 (Manchado et al 2016), BCL-XL (Corcoran et al 2013), YAP1 (Lin et al 2015) and PTPN11 (Prahallad et al 2015). …”

Cytokines and Metabolic Factors Regulate Tumoricidal T-Cell Function During Cancer Immunotherapy

“…For instance, treating metastatic melanomas harboring the common BRAF(V600E) mutation with a small-molecule inhibitor leads to tumor regression followed by recurrence of tumors capable of bypassing BRAF to activate downstream mitogenic MAPK signaling, but importantly these future science group Review Adler, Mittal, Ryan, Zhou, Wasser & Vella variant tumors can be responsive to cotreatment with an MEK inhibitor [4]. Similarly, KRAS-mutant lung tumors develop resistance to MEK inhibition via compensatory mitogenic signals received through FGFR1 and thus become susceptible to FGFR1 inhibition [97]. Given the reciprocal effects, checkpoint inhibitors and costimulatory agonists have in regulating T-cell responsiveness by relieving negative and potentiating positive signals, respectively, it was perhaps logical that combining biologics from each class do enhance therapeutic efficacy [82][83][84].…”