Comprehensive mutation profiling and novel therapeutic insights in lung cancer

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We addressed a significant gap in the field by profiling EGFR and KRAS mutation frequencies in approximately 1,000 samples from Indian lung cancer patients. Our findings revealed 23% EGFR and 19% KRAS mutations, with a 74% clinical response to EGFR tyrosine kinase inhibitors, which is markedly distinct from the previously known Caucasian (10-15%) and East-Asian populations (30-50%).

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  Figure: Schematic representation of genomic landscape of lung cancer in the Indian subcontinent. 

 

Subsequently, we described the first comprehensive landscape of actionable mutations across ~450 lung adenocarcinoma cases. Our work, using sophisticated genetic, biochemical, and mouse-xenograft-based mechanistic characterization, led to the discovery of novel FGFR3 activating mutations in lung adenocarcinoma patients of Indian origin. Subsequently, we systematically identified EGFR, PIK3CA, and FGFR1 as therapeutic targets and mapped the global landscape of alterations in ~450 Indian lung squamous cancer cases. Our research shows that treating lung squamous cancer cells with focally amplified FGFR1 and lung adenocarcinoma cells with FGFR3 mutations using FGFR-specific shRNAs or small molecule inhibitors leads to cell growth inhibition, opening the possibility of subtype-specific lung cancer treatments targeting FGFR family genes.

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More recently, we developed a mouse system to model the ADAURA clinical trial by injecting luciferase-tagged lung cancer cells through the mouse tail vein, colonizing the lungs within 24 hours. The ADAURA trial established that daily dosing of adjuvant osimertinib in early-stage lung cancer could significantly delay relapse. However, our findings suggest that daily dosing of adjuvant osimertinib may not be necessary.

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Currently, our efforts are focussed to identify the mechanisms of resistance in EGFR and ALK inhibitors by using an integrated genomic approach on tumor biopsies from patients, both TKI-naïve and resistant, to discover mutations or deregulated genes associated with resistance. Detailed functional validation of candidate genes are underway through genetic perturbation and in vitro assays, with findings extended to xenograft mouse models to improve patient treatment selection and develop effective therapies for TKI-resistant lung cancer.

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Publications:

 

18. Chougule A, Chandrani P, Noronha V, Pange P, Kale S, Nikam A, Nambiar K, Marchande D, Durve A, Gupta V, Jagtap V, Tiwrekar P, Menon N, Joshi A, Kaushal R, Pai T, Patil VM, Dutt A, Banavali SD, Prabhash K. Real-World Evidence of EGFR Targeted Therapy in NSCLC- A Brief Report of Decade Long Single Center Experience. JTO Clin Res Rep. 2023 Aug 23;4(11):100566. ​

 

17. Noronha V, Chougule A, Chandrani P, Kaushal RK, Patil VM, Menon N, Kapoor A, Chopade S, Singh A, Shetty O, Dutt A, Banavali S, Prabhash K. Lung cancer with dual EGFR and ALK driver alterations at baseline: a retrospective observational cohort study. Acta Oncol. 2022 Sep;61(9):1143-1147

 

16. Joshi A, Butle A, Hait S, Mishra R, Trivedi V, Thorat R, Choughule A, Noronha V, Prabhash K, Dutt A. Osimertinib for lung cancer cells harboring low-frequency EGFR T790M mutation. Transl Oncol. 2022 Aug;22:101461. 

 

​15. Butle A, Joshi A, Noronha V, Prabhash K, Dutt A. Weekly osimertinib dosing prevents EGFR mutant tumor cells destined to home mouse lungs. Transl Oncol. 2021 Aug;14(8):101111. 

 

​14. Joshi A, Mishra R, Desai S, Chandrani P, Kore H, Sunder R, Hait S, Iyer P, Trivedi V, Choughule A, Noronha V, Joshi A, Patil V, Menon N, Kumar R, Prabhash K, Dutt A. Molecular characterization of lung squamous cell carcinoma tumors reveals therapeutically relevant alterations. Oncotarget. 2021 Mar 16;12(6):578-588. 

 

13. Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, Janu A, Purandare N, Kumar R, More S, Goud S, Kadam N, Daware N, Bhattacharjee A, Shah S, Yadav A, Trivedi V, Behel V, Dutt A, Banavali SD, Prabhash K. Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Mutated Lung Cancer. J Clin Oncol. 2020 Jan 10;38(2):124-136. 

 

12. Veldore VH, Choughule A, Routhu T, Mandloi N, Noronha V, Joshi A, Dutt A, Gupta R, Vedam R, Prabhash K. Validation of liquid biopsy: plasma cell-free DNA testing in clinical management of advanced non-small cell lung cancer. Lung Cancer (Auckl). 2018 Jan 3;9:1-11. 

 

11. Chandrani P, Prabhash K, Prasad R, Sethunath V, Ranjan M, Iyer P, Aich J, Dhamne H, Iyer DN, Upadhyay P, Mohanty B, Chandna P, Kumar R, Joshi A, Noronha V, Patil V, Ramaswamy A, Karpe A, Thorat R, Chaudhari P, Ingle A, Choughule A, et al. Drug-sensitive FGFR3 mutations in lung adenocarcinoma. Ann Oncol. 2017 Mar 1;28(3):597-603. 

 

10. Ramteke MP, Patel KJ, Godbole M, Vyas M, Karve K, Choughule A, Prabhash K, Dutt A. CRE: a cost effective and rapid approach for PCR-mediated concatenation of KRAS and EGFR exons: Rapid way to detect EGFR and KRAS mutations. Version 2. F1000Res. 2015 Jun 23 [revised 2016 Jan 1];4:160. 

 

9. Choughule A, Sharma R, Trivedi V, Thavamani A, Noronha V, Joshi A, Desai S, Chandrani P, Sundaram P, Utture S, Jambhekar N, Gupta S, Aich J, Prabhash K, Dutt A. Coexistence of KRAS mutation with mutant but not wild-type EGFR predicts response to tyrosine-kinase inhibitors in human lung cancer. Br J Cancer. 2014 Nov 25;111(11):2203-4. ​

 

8. Chougule A, Prabhash K, Noronha V, Joshi A, Thavamani A, Chandrani P, Upadhyay P, Utture S, Desai S, Jambhekar N, Dutt A. Frequency of EGFR mutations in 907 lung adenocarcioma patients of Indian ethnicity. PLoS One. 2013 Oct 4;8(10):e76164.

 

7. Choughule A, Noronha V, Joshi A, Desai S, Jambhekar N, Utture S, Thavamanni A, Prabhash K, Dutt A. Epidermal growth factor receptor mutation subtypes and geographical distribution among Indian non-small cell lung cancer patients. Indian J Cancer. 2013 Apr-Jun;50(2):107-11. 

 

6. Noronha V, Prabhash K, Thavamani A, Chougule A, Purandare N, Joshi A, Sharma R, Desai S, Jambekar N, Dutt A, Mulherkar R. EGFR mutations in Indian lung cancer patients: clinical correlation and outcome to EGFR targeted therapy. PLoS One. 2013 Apr 19;8(4):e61561. 

 

5. Hammerman PS, Sos ML, Ramos AH, Xu C, Dutt A, Zhou W, Brace LE, Woods BA, Lin W,  Zhang J, Deng X, Lim SM, Heynck S, Peifer M, Simard JR, Lawrence MS, Onofrio RC, Salvesen HB, Seidel D, Zander T, Heuckmann JM, Soltermann A, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011 Jun;1(1):78-89. 

 

4. Dutt A, Ramos AH, Hammerman PS, Mermel C, Cho J, Sharifnia T, Chande A, Tanaka KE, Stransky N, Greulich H, Gray NS, Meyerson M. Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS One. 2011;6(6):e20351.

 

3. Ramos AH, Dutt A, Mermel C, Perner S, Cho J, Lafargue CJ, Johnson LA, Stiedl AC, Tanaka KE, Bass AJ, Barretina J, Weir BA, Beroukhim R, Thomas RK, Minna JD, Chirieac LR, Lindeman NI, Giordano T, Beer DG, Wagner P, Wistuba II, Rubin MA, et al. Amplification of chromosomal segment 4q12 in non-small cell lung cancer.Cancer Biol Ther. 2009 Nov;8(21):2042-50. 

 

2. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008 Oct 23;455(7216):1069-75. 

 

1. Dutt A, Wong KK. Mouse models of lung cancer. Clin Cancer Res. 2006 Jul 15;12(14 Pt 2):4396s-4402s. Review.