The ALK tyrosine kinase inhibitor (TKI), crizotinib, shows significant activity in patients whose lung cancers harbor ALK fusions but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the intriguing clinical observation of a patient with ALK fusion+ lung cancer who had an ‘exceptional response’ to an IGF-1R antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor, IRS-1, and IRS-1 knockdown enhances the anti-tumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK/IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, IGF-1R/IRS-1 levels are increased in biopsy samples from patients progressing on crizotinib therapy. Collectively, these data support a role for the IGF-1R/IRS-1 pathway in both ALK TKI-sensitive and TKI-resistant states and provide biological rationale for further clinical development of dual ALK/IGF-1R inhibitors.

Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKIs) with documented anti-tumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration.

Introduction Patients with small cell lung cancer (SCLC) have a poor prognosis and limited treatment options. Since access to longitudinal tumor samples is very limited in patients with this disease, we chose to focus our studies on the characterization of plasma cell-free DNA (cfDNA) for rapid, noninvasive monitoring of disease burden. Methods We developed a liquid biopsy assay that quantifies somatic variants in cfDNA. The assay detects single nucleotide variants, copy number alterations, and insertions or deletions in 14 genes that are frequently mutated in SCLC, including TP53, RB1, BRAF, KIT, NOTCH1–4, PIK3CA, PTEN, FGFR1, MYC, MYCL1, and MYCN. Results Over 26 months of peripheral blood collection, we examined 140 plasma samples from 27 patients. We detected disease-associated mutations in 85% of patient samples with mutant allele frequencies (AFs) ranging from ≤0.1% to 84%. In our cohort, 59% of the patients had extensive stage disease, and the most common mutations occurred in TP53 (70%) and RB1 (52%). In addition to mutations in TP53 and RB1, we detected alterations in 10 additional genes in our patient population (PTEN, NOTCH1–4, MYC, MYCL1, PIK3CA, KIT, and BRAF). Observed AFs and CNAs tracked closely with treatment responses. Notably, in several cases analysis of cfDNA provided evidence of disease relapse before conventional imaging. Conclusions These results suggest that liquid biopsies are readily applicable in patients with SCLC and can potentially provide improved monitoring of disease burden, depth of responses to treatment, and timely warning of disease relapse in patients with this disease.

Mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of EGFR-mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with EGFR-mutant lung cancer. Despite promising results, therapeutic efficacy is limited by development of acquired resistance. Here we report that Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and mitogen-activated protein kinase (MAPK) pathway signaling under continuous EGFR inhibition in osimertinib sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member YES1 was amplified in osimertinib- resistant EGFR-mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors. In conclusion, our data suggest that concomitant inhibition of both SFK/FAK and EGFR may be a promising therapeutic strategy for EGFR-mutant lung cancer.

Purpose: The third-generation EGFR inhibitor, osimertinib, is the first mutant-selective inhibitor that has received regulatory approval for the treatment of patients with EGFR-mutant lung cancer. Despite the development of highly selective thirdgeneration inhibitors, acquired resistance remains a significant clinical challenge. Recently, we and others have identified a novel osimertinib resistance mutation, G724S, which was not predicted in in vitro screens. Here, we investigate how G724S confers resistance to osimertinib. Experimental Design: We combine structure-based predictive modeling of G724S in combination with the 2 most common EGFR-activating mutations, exon 19 deletion (Ex19Del) and L858R, with in vitro drug-response models and patient genomic profiling. Results: Our simulations suggest that the G724S mutation selectively reduces osimertinib-binding affinity in the context of Ex19Del. Consistent with our simulations, cell lines transduced with Ex19Del/G724S demonstrate resistance to osimertinib, whereas cells transduced with L858R/ G724S are sensitive to osimertinib. Subsequent clinical genomic profiling data further suggest G724S occurs with Ex19Del but not L858R. Furthermore, we demonstrate that Ex19Del/G724S retains sensitivity to afatinib, but not to erlotinib, suggesting a possible therapy for patients at the time of disease relapse. Conclusions: Altogether, these data suggest that G724S is an allele-specific resistance mutation emerging in the context of Ex19Del but not L858R. Our results fundamentally reframe the problem of targeted therapy resistance from one focused on the "drug-resistance mutation" pair to one focused on the "activating mutation-drug-resistance mutation" trio. This has broad implications across clinical oncology.