Substantial population and preclinical data have indicated that the insulin growth factor (IGF) pathway plays an important role in lung cancer. Although results from early clinical trials targeting the IGF1R showed some evidence of response in non-small cell lung cancer (NSCLC), larger randomized phase III trials have not shown clear clinical benefit in combination with conventional strategies. These disappointing results have focused attention on the insulin receptor isoform A (IR-A) as one intrinsic resistance factor to anti-IGF1R therapy due to its ability to mediate growth-promoting signaling through binding to IGF-II. However, the expression status of insulin-receptor isoforms in lung cancer and its subtypes is largely unknown. In order to address this issue, the mRNA expression levels of insulin-receptor isoforms were studied in 50 normal lung samples and 183 lung cancer samples from complementary DNA (cDNA) arrays. Additionally, 31 primary small cell lung cancer (SCLC) tumor samples with paired adjacent normal tissues were also evaluated.

The mRNA expression levels of insulin receptor isoform B (IR-B) were significantly lower in NSCLC than normal lung samples (n=176, p < 0.001), including adenocarcinoma (n=85, p < 0.0001), squamous cell carcinoma (n=60, p < 0.0001) and large cell lung cancer samples (n=16, p < 0.0001). The mRNA expression levels of IR-B were also significantly lower in SCLC primary tumor samples (P=0.002).

The mRNA levels for IR-A were significantly higher in primary SCLC samples (p < 0.02) than paired adjacent normal, but no significant differences between normal lung and NSCLC or its subtypes were observed (p > 0.05).

When comparing tumor to normal lung samples, the IR-A:IR-B mRNA expression ratios were significantly higher in primary SCLC samples (p <0.0001). The IR-A:IR-B mRNA expression ratios were also significantly higher in all NSCLC samples compared to normal lung, (p < 0.001) including adenocarcinoma (p < 0.0001), squamous cell carcinoma (p < 0.0001) and large-cell lung cancer (p < 0.0001).

Our results indicated that the reduction of the level of IR-B expression and an increase in the IR-A:IR-B expression ratio may highlight patients with active IR-A signaling, and may be more informative than identifying those with increased IR-A expression only. Additionally, these results suggested that an increased IR-A:IR-B expression ratio might be a useful biomarker in selecting patients that may have an intrinsic resistance to anti-IGF1R therapy in lung cancer.

Citation Format: Jiaqi Huang, Katie Streicher, Chris Morehouse, Kim Lehmann, Philip Brohawn, Wei Zhu, Meggan Czapiga, Theresa LaVallee, Karen Mitz, Laura Richman, Bahija Jallal, Yihong Yao. Differential expression of insulin receptor isoforms in human lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5268. doi:10.1158/1538-7445.AM2013-5268