Dacomitinib, but Not Lapatinib, Suppressed Progression in Castration-resistant Prostate Cancer Models by Preventing HER2 Increase

Overexpression and activation of the EGFR family members EGFR and HER2/ErbB2 has been observed in numerous cancer types, including prostate cancer, where they promote a castration-resistant phenotype, leading to accelerated tumor growth and metastasis (Day et al, 2017, Canc Res). They were thus considered a suitable target for therapy. Unfortunately, first-generation, reversible EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib and EGFR/HER2 dual-kinase inhibitors such as lapatinib showed little efficacy when tested in clinical trials of patients with castration-resistant prostate cancer (CRPC). One reason may have been their inability to impair EGFR and HER2 kinase activity at the concentrations administered. A second reason may have been their inability to decrease EGFR and HER2 protein levels. We recently provided the first evidence that extremely low doses of the second generation, irreversible EGFR TKI, dacomitinib showed superior efficacy in a panel of human CRPC cell lines preclinical studies by virtue of its ability to impair EGFR and HER2 kinase activity and decrease EGFR and HER2 protein levels.

Despite the central role of the androgen receptor (AR) in driving prostate tumor growth, targeting EGFR remains an area of active investigation. Genomic analyses of men with metastatic prostate cancer have demonstrated frequent amplifications in MET and EGFR¹ whereas patients with metastatic CRPC (mCRPC) display an enrichment of multiple genes involved in MAP/ERK signaling, including EGFR.² EGFR has also been found in exosomes of prostate cancer patients, where it may mediate cell invasion and tumor proliferation leading to therapy resistance.³

Examples of novel methods of decreasing EGFR transcript levels include using aptamer-siRNA⁴ and microRNAs,⁵ leading to downregulation of EGFR protein and eventual tumor shrinkage via apoptotic cell death. Katreddy et al⁶ demonstrate that the failure of EGFR TKIs via innate or acquired resistance results from kinase-independent functions of EGFR, and that pharmacological downregulation of EGFR protein levels rather than inhibition of its kinase activity may be the key to treating EGFR-positive tumors, an idea that was also proposed over a decade ago.⁷ By demonstrating that one mechanism of TKI (ie dacomitinib) efficacy involves a significant reduction of EGFR protein levels, we believe our work supports these conclusions, strengthening the case for continuing to pursue EGFR targeting as a potential therapeutic option for CRPC patients.

Written by: Maitreyee K Jathal, PhD, Postdoctoral scholar, Paediatric Cancer Biology, University of California Davis, Sacramento, CA and Paramita M Ghosh, PhD, VA Northern California Health Care System, Mather, CA; University of California Davis, Sacramento, CA

References:
1. Edwin Lin et al, "Profiling of genomic alterations in MAPK/ERK signaling in a large cohort of metastatic prostate cancer (mPC) patients." J Clin Oncol 37, 2019 (suppl; abstr 5032), June 1, 2019, https://meetinglibrary.asco.org/record/175757/abstract
2. Andrew W Hahn et al, "Genomic landscape of metastatic hormone sensitive prostate cancer (mHSPC) vs. metastatic castration-refractory prostate cancer (mCRPC) by circulating tumor DNA (ctDNA)." J Clin Oncol 37, 2019 (suppl; abstr 5043), June 1, 2019. https://meetinglibrary.asco.org/record/175772/abstract
3. Kharmate G et al, "Epidermal Growth Factor Receptor in Prostate Cancer Derived Exosomes." Plos One, doi.org/10.1371/journal.pone.0154967, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154967
4. Hong Yan Liu et al, "Co-targeting EGFR and survivin with a bivalent aptamer-dual siRNA chimera effectively suppresses prostate cancer." Scientific Reports volume6, Article number: 30346, July 26, 2016, https://www.nature.com/articles/srep30346
5. Bin Xu et al, "hsa-miR-135a-1 inhibits prostate cancer cell growth and migration by targeting EGFR." Tumor Biology October 2016, Volume 37, Issue 10, pp 14141–14151, August 14, 2016, https://link.springer.com/article/10.1007/s13277-016-5196-6.
6. Rajasekhara Reddy Katreddy et al, "Targeted reduction of the EGFR protein, but not inhibition of its kinase activity, induces mitophagy and death of cancer cells through activation of mTORC2 and Akt." Oncogenesisvolume 7, Article number: 5 (2018), January 23, 2018. https://www.nature.com/articles/s41389-017-0021-7
7. Zhang Weihua et al, "Survival of Cancer Cells Is Maintained by EGFR Independent of Its Kinase Activity." Cancer Cell, doi: 10.1016/j.ccr.2008.03.015, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2413063/.

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