Fellows' research : Identification of novel mutations show potential for targeted therapy treatment of gallbladder cancer


30 Nov 2018

Fellows' research : Identification of novel mutations show potential for targeted therapy treatment of gallbladder cancer

 

Dr. Amit Dutt, Intermediate Fellow

Tata Memorial Centre, ACTREC, Mumbai

Our research, published in International Journal of Cancer, presents the first genomic landscape of early-stage gallbladder cancer (GBC) in the Indian population and implicates the gene, ERBB2, as an important therapeutic candidate and suggests the adoption of a type of targeted anti-cancer therapy routinely used in case of colorectal cancer, to treat patients with GBC.

Among cancers of the human biliary tract, GBC is the most common and aggressive type with dismal treatment options. Complete surgical resection is the only curative modality; however, only 10% of the patients with GBC present with early-stage disease qualify for surgical intervention. Although GBC is rare globally, a distinct high incidence is recorded in certain world populations including in India, particularly in the Gangetic plains in North India. Incidence rates in Delhi (~21.5 per 100,000 women) are the highest in the world!  

We earlier proposed a gallbladder carcinogenesis and dissemination model according to which dysplasia (i.e. abnormal growth of cells), a premalignant lesion, could potentially develop into carcinoma in situ and invasive gallbladder adenocarcinoma1. However, the ‘inflammatory stimulus’ to drive the initial cascade in this model remained unclear. Subsequently, we presented the first evidence to support that non-typhoidal Salmonella species with typhoidal isolates likely provide the ‘inflammatory stimulus’ and play a role in gallbladder cancer2analogous to Helicobacter pylori in gastric cancer and Fusobacterium in colon cancer.

In our recently published study3, we performed a comprehensive characterization of the pattern and rate of somatic mutations in Indian patients with GBC. Additionally, we characterized intricate functional aspects of the disease using cutting-edge technologies such as whole exome sequencing, unbiased characterization of activated kinases, and elegant genetic and biochemical perturbation cell-based assays including mouse xenograft assays.

Our study shows that the survival of gallbladder cells essentially depends on the activation of the ErbB signalling pathway. We report activating ERBB2 alterations in 40% early-stage rare gallbladder tumours and co-occurring KRAS mutation in 7% of the tumours. KRAS is a gene responsible for regulating cell proliferation.

Over-expression of EGFR has been observed in various cancers and has therefore been employed as an important drug target. We demonstrate that a complex formed between ERBB2 and EGFR constitutively activates the ErbB signalling pathway in gallbladder cells.

We have used both cell-based assay and biochemical analysis to support our genomic discovery using in vitro and in vivo murine systems. Interestingly, the genetic and pharmacological dependencies of gallbladder cells on ErbB signalling were found to be dependent on the KRAS mutant allele status. Based on ERBB2 alteration, anti-EGFR therapy is an option for treating GBC; however, the presence of the KRAS mutations may impede treatment response, reminiscent of the clinical algorithm commonly practiced to choose anti-EGFR treatment in colorectal cancer.

Overall, the functional biology of activating ERBB2 and KRAS somatic mutations in gallbladder tumours presented in this study identify ERBB2 as an important therapeutic target under neo-adjuvant or adjuvant settings. We also present the first evidence that the presence of KRAS mutations (presence of KRAS (G12V), but not KRAS (G13D)) may preclude patients with GBC to respond to anti-EGFR treatment, similar to a clinical algorithm commonly practiced to decide on anti-EGFR treatment in colorectal cancer.

References:

            1. A genetic model for gallbladder carcinogenesis and its dissemination.Barreto SG, Dutt A, Chaudhary A.  Annals of oncology : official journal of the European Society for Medical Oncology 2014

            2. Non-typhoidal Salmonella DNA traces in gallbladder cancer. Iyer P, Barreto SG, Sahoo B, Chandrani P, Ramadwar MR, Shrikhande SV, Dutt A. Infectious agents and cancer. 2016

            3. ERBB2 and KRAS Alterations Mediate Response to EGFR Inhibitors in Early Stage Gallbladder Cancer. Iyer P, Shrikhande SV, Ranjan M, Joshi A, Gardi N, Prasad R, Dharavath B, Thorat R, Salunkhe S, Sahoo B, Chandrani P, Kore H, Mohanty B, Chaudhari V, Choughule A, Kawle D, Chaudhari P, Ingle A, Banavali S, Gera P, Ramadwar MR, Prabhash K, Barreto SG, Dutt S, Dutt AInternational Jorunal of Cancer. October 2018.

Banner Credits: Wellcome Collection. Cancer of the gall bladder.