C. J. Tignanelli1, J. Stratford2,3, R. A. Moffitt2, J. Yeh1,2,3 1University Of North Carolina At Chapel Hill,Department Of Surgery,Chapel Hill, NC, USA 2University Of North Carolina At Chapel Hill,Lineberger Comprehensive Cancer Center,Chapel Hill, NC, USA 3University Of North Carolina At Chapel Hill,Department Of Pharmacology,Chapel Hill, NC, USA
Introduction:
Resistance to single kinase inhibition is one of the main challenges in the treatment of cancer patients. We have previously shown that treatment with BKM120 (a pan-class 1 PI3K inhibitor, currently in Phase I/II clinical trials) resulted in tumor growth inhibition (p = 0.017) but not regression in a pancreatic ductal adenocarcinoma (PDAC) patient derived xenograft (PDX) mouse model, suggesting that tumors may be adapting to PI3K inhibition. When evaluating possible mechanisms of resistance we identified ErbB1, ErbB2 and ErbB3 activation in response to BKM120 treatment in both cell lines and PDX tumors. The ErbB family is a well-established therapeutic target in multiple cancers. Intense cross-talk is known to occur between ErbB isoforms perhaps contributing to the limited effectiveness of single ErbB inhibition seen in the clinic in the case of erlotinib in PDAC. We hypothesized that pan-ErbB inhibition would be required in combination with BKM120 for optimal tumor response.
Methods:
PDAC cell lines were treated with 475 nM of BKM120 and either 25 nM of siErbB1, siErbB2, siErbB3, or 40nM dacomitinib (a pan-ErbB inhibitor currently in Phase III clinical trials). Target inhibition was confirmed by immunoblotting. Cellular viability was measured using a cellular growth assay after 72 hours of treatment.
Results:
We found that the combination of BKM120 and dacomitinib inhibited proliferation in 10 of 10 PDAC cell lines (p < 0.01) and was more effective than BKM120 alone. Furthermore, BKM120 and dacomitinib showed impressive synergy across all cell lines with a mean combination index of 0.24 (0.00245 – 0.49). We next evaluated whether inhibition of any single ErbB family member would be sufficient for synergy with BKM120. We observed significantly greater growth inhibition after treatment with BKM120 and dacomitinib (68%) in the HPAC cell line compared with BKM120 + siErbB1 (48%, p < 0.001), BKM120 + siErbB2 (51%, p < 0.001), or BKM120 + siErbB3 (55%, p = 0.002), suggesting that single ErbB inhibition is not as effective as pan-ErbB inhibition.
Conclusion:
Our results suggest that inhibition of any single ErbB will not be sufficient to overcome the adaptive response of tumors to PI3K inhibition. Instead, combined treatment with a pan-ErbB and PI3K inhibitor will be necessary. Combination studies in PDX models are ongoing. Pan-ErbB and PI3K inhibition in PDAC may be more effective than either single agent alone and should be considered in clinical trials.