The Z<sub>HER2:V2</sub>-pemetrexed conjugate could inhibit tumor growth of HER2-positive lung adenocarcinoma and may have the potential to become a targeted drug for lung cancer.
The variable responses to anti-HER2 therapies in these patients prompt us to examine impact of <i>HER2</i> variants and co-mutations on responses to anti-HER2 treatments in lung cancer.
Patients with lung cancer and HER2 mutations developed more brain metastases on treatment than patients with KRAS mutations (28% vs 8%; hazard ratio [HR], 5.2; P < .001) and trended more than patients with EGFR mutations (28% vs 16%; HR, 1.7; P = .06).
We examined changes in CTC numbers and morphology early after targeting therapy in EGFR-mutated PC-9 human lung cancer and HER2-gene amplified GLM-1 gastric cancer mouse CTC models using a cytology-based semi-automated CTC detection platform.
To assess antigen reactivity, <sup>89</sup>Zr-DFO-trastuzumab was evaluated using the Lindmo method and tested in PET/CT imaging of mouse models of human epidermal growth factor receptor 2-positive or -negative lung cancer.
Overlapping with ERBB2-associated human lung cancer genes further identified those ERBB2 downstream players potentially conserved in human and mouse lung tumors.
Germline mutations in EGFR and erb-b2 receptor tyrosine kinase 2 (ERBB2) have been previously reported in lung cancers that may be associated with genetic susceptibility to lung cancer.
The present study involves ligand-based pharmacophore modeling of various kinases, including EGFR (T790 M), cMET, ErbB2, FGFR and ALK, which are well established targets of normal as well resistant lung cancer.
In contrast, afatinib and neratinib were predicted to be more effective than other inhibitors for the A775_776insYVMA mutation, the most frequent <i>ERBB2</i> mutation in lung cancer.
Results suggested that the conjugate exhibited selective antiproliferative activity in HER2-overexpressing breast and lung cancer cell lines and was able to block HER2:HER3 heterodimerization.
Among these, a symmetrical cyclic peptidomimetic (compound 18) exhibited antiproliferative activity in HER2-overexpressing lung cancer cell lines with IC<sub>50</sub> values in the nanomolar concentration range.
The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas.<b>Experimental Design:</b> Sixteen U.S. institutions enrolled 1,367 patients with lung cancer in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and IHC.<b>Results:</b> The use of targeted therapies in patients with <i>EGFR, ERBB2,</i> or <i>BRAF</i> p.V600E mutations, <i>ALK, ROS1</i>, or <i>RET</i> rearrangements, or <i>MET</i> amplification was associated with a survival increment of 1.5 years compared with those with such mutations not receiving targeted therapy, and 1.0 year compared with those lacking a targetable driver.
Activating EGFR mutations, HER2, and HER3 are implicated in lung cancer; however, with the exception of EGFR gene amplification in lung adenocarcinoma harboring EGFR mutations, their involvement in disease progression during the early stages is poorly understood.
The peptidomimetic (Cyclo(1,10)PpR (<i>R</i>) Anapa-FDDF-(<i>R</i>)-Anapa)R, compound 18) was shown to exhibit antiproliferative activity with an IC<sub>50</sub> of 194 nM in HER2-expressing breast cancer cell lines and 18 nM in lung cancer cell lines.
Herein, the authors describe the prevalence, clinical features, and outcomes associated with HER2 mutations in 1007 patients in the Lung Cancer Mutation Consortium (LCMC).