First comprehensive description of druggable mutation spectrum in lung cancer patients in India

01 Jan 2017

First comprehensive description of druggable mutation spectrum in lung cancer patients in India

First comprehensive description of druggable mutation spectrum in lung cancer patients in India

Dr Amit Dutt, Intermediate Fellow

Tata Memorial Centre - Advanced Centre for Treatment, Research and Education in Cancer

The observed mutational diversity underlying cancer genomes is in line with the varied clinical response found in cancer patients based on their ethnicity, divergent genetic structure and exposure to environmental factors. Therefore, besides the unmet need for additional therapeutic targets in lung cancer patients, it is equally important to screen for and profile known therapeutically targetable gene alterations across different populations to acquire a better understanding of this landscape of variability. In the study published in Annals of Oncology by our group with other colleagues from ACTREC, Tata Memorial Centre, we addressed this germane and basic deficiency in the field by profiling for known actionable mutations in 363 Indian lung cancer patients using advanced sequencing technologies and Mass Spectrometry.

Our findings present the first comprehensive description of actionable mutation spectrum in lung cancer patients, which interestingly occurs at markedly distinct frequency in Indian population compared to the previously known Caucasian and East-Asian populations. The crucial findings from this study form the base to rationalize targeted therapy among Indian lung cancer patients. This study also presents the first systematic evidence for occurrence of recurring mutations in a receptor tyrosine kinase gene, fibroblast growth factor receptor 3 (FGFR3) in 20 of 363 (5.5%) lung adenocarcinoma patients studied. FGFR3 mutations have been reported in bladder carcinoma, lung squamous cell carcinomas (a different subtype of lung cancer), and cervical cancer, but were found to be largely absent in lung adenocarcinoma patients of Caucasian origin. More recently, consistent with our previous study, presence of frequent FGFR3 mutations, have been tangentially referred to, also exist in Korean lung adenocarcinomas patients. However, details of the mutations described in this study remain to be defined. Thus, our finding along with the indirect reference of similar mutation in Korean population suggests an emerging role for FGFR3 mutations in lung adenocarcinoma that are more likely to be predominant among the Asian population

In this study we provide detailed mechanistic characterization of the novel FGFR3 activating mutations found in lung adenocarcinoma patients using elegant genetic, biochemical and mouse-xenograft experimental techniques. This study concludes that the FGFR3 mutations found in lung adenocarcinoma patients of Indian origin are oncogenic, and form a subclass of FGFR inhibitor-sensitive patients largely distinct from those harboring other druggable mutations in lung cancer, such as these in EGFR, KRAS, or EML4-ALK mutations.

Interestingly, the FGFR3 mutations appear to be significantly higher in proportion in patients less than 45 years old (P value = 0.048), and show a trend towards better overall survival of 17 months (P value= 0.5) compared to patients lacking actionable alterations or those harboring KRAS mutations. Taken together, these findings implicate FGFR3 as a novel and an effective therapeutic target in treating lung adenocarcinoma patients.


Figure: Left panel: Pie-chart representation of the frequency of clinically relevant genes observed in 363 Indian lung adenocarcinoma patients. Right upper panel: PET scan to assess 18F-FDG uptake by tumors obtained by subcutaneous injection of mouse embryonic fibroblast cells (NIH/3T3) clones over expressing FGFR wild type and mutant constructs ~2 months. Selective FGFR inhibitor BGJ-398 or vehicle treatment was administered orally in mice after tumor size reaching ~100-200 mm3, for 21 days. A readout for relative 18F-FDG uptake is shown by a gradient color code with red indicating as maximum uptake. 18-Fluoro-deoxyglucose positron emission tomography or 18F-FDG/PET scan is used for imaging tumors and is based on the amount of glucouse uptake by tumours which reflect its metabolic state. Right lower panel: Immuno-histochemical staining of total- and phospho- ERK1/2 is shown in xenografts treated with drug and vehicles. Phospho- ERK1/2 is used as a marker to study cell proliferation, found to be over-activated in tumours. 

Drug-sensitive FGFR3 mutations in lung adenocarcinoma. P. Chandrani, K. Prabhash, A. Choughule, R. Prasad, V. Sethunath, M. Ranjan, P. Iyer, J. Aich, H. Dhamne, D. N. Iyer, P. Upadhyay, B. Mohanty, P. Chandna, R. Kumar, A. Joshi, V. Noronha, V. Patil, A. Ramaswamy, A. Karpe, R. Thorat, P. Chaudhari, A. Ingle and A. Dutt. Annals of Oncology. Dec 2016