Combined effect of cabozantinib and gefitinib in crizotinib‐resistant lung tumors harboring ROS1 fusions

Abstract

The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non‐small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2‐ROS1 and ABC‐20 harboring CD74‐ROS1, were used as cell line‐based resistance models. Crizotinib‐resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor‐receptor tyrosine kinase array and RNA sequence analysis by next‐generation sequencing. HCC78R cells showed upregulation of HB‐EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB‐EGF or EGF rendered HCC78 cells or ABC‐20 cells resistant to crizotinib. RNA sequence analysis by next‐generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR‐TKI or anti‐EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR‐TKI were more effective against HCC78R cells than monotherapy with an EGFR‐TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB‐EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR‐TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.

VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene‐driven non‐small‐cell lung cancers

“…H3122 ( EML4‐ALK fusion) and HCC78 ( SLC34A2‐ROS1 fusion) cells were kindly provided by William Pao (Vanderbilt University, Nashville, TN, USA). ABC‐11 ( EML4‐ALK fusion) and ABC‐20 ( CD74‐ROS1 fusion) cells were established from NSCLC patients in our laboratory 12,13 . All cell lines were cultured in RPMI‐1640 medium (Sigma‐Aldrich) supplemented with 10% heat‐inactivated fetal bovine serum and 1% penicillin/streptomycin; cells were maintained at 37°C in a 5% CO 2 humified atmosphere.…”

Cabozantinib (XL184) and R428 (BGB324) Inhibit the Growth of Esophageal Squamous Cell Carcinoma (ESCC)

“…It has been approved in the USA to treat advanced renal cell carcinoma (RCC) and locally advanced or metastatic medullary thyroid cancer (MTC) (22, 23). The anti-tumor activity of cabozantinib has also been demonstrated in preclinical studies for breast cancer (24, 25), prostate cancer (25, 26), hepatocellular carcinoma (HCC) (27, 28), lung cancer (29), and bladder cancer (30). Its efficacy has also been demonstrated in phase II clinical trials for NSCLC (17, 31) and in phase III trials for advanced HCC (32).…”

ROS1-ADGRG6: a case report of a novel ROS1 oncogenic fusion variant in lung adenocarcinoma and the response to crizotinib

“…For example, ROS1 fusions results in transformation of NIH3T3 in vitro and tumorigenicity in vivo [10, 11]. Transgenic mice harboring EZR-ROS1 in the lung alveolar epithelial cells develop bilateral lung adenocarcinomas [12, 13]. Indeed, ROS1-ADGRG6 rearrangement has not been previously reported in lung cancer, thus this is the first report of a novel ROS1 fusion variant.…”