Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer
Chemotherapy resistance is a major obstacle in cancer treatment, yet the mechanisms of response to specific therapies have been largely unexplored in vivo. Employing genetic, genomic, and imaging approaches, we examined the dynamics of response to a mainstay chemotherapeutic, cisplatin, in multiple...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Cold Spring Harbor Laboratory Press in association with The Genetics Society
2011
|
| Online Access: | http://hdl.handle.net/1721.1/64761 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-2693-4982 |
| _version_ | 1811096759262248960 |
|---|---|
| author | Oliver, Trudy Mercer, Kim L. Sayles, Leanne C. Burke, James R. Mendus, Diana Lovejoy, Katherine S. Cheng, Mei-Hsin Subramanian, Aravind Mu, David Powers, Scott Crowley, Denise G. Bronson, Roderick T. Whittaker, Charles A. Bhutkar, Arjun (AJ) Lippard, Stephen J. Golub, Todd R. Thomale, Juergen Jacks, Tyler E. Sweet-Cordero, E. Alejandro |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Oliver, Trudy Mercer, Kim L. Sayles, Leanne C. Burke, James R. Mendus, Diana Lovejoy, Katherine S. Cheng, Mei-Hsin Subramanian, Aravind Mu, David Powers, Scott Crowley, Denise G. Bronson, Roderick T. Whittaker, Charles A. Bhutkar, Arjun (AJ) Lippard, Stephen J. Golub, Todd R. Thomale, Juergen Jacks, Tyler E. Sweet-Cordero, E. Alejandro |
| author_sort | Oliver, Trudy |
| collection | MIT |
| description | Chemotherapy resistance is a major obstacle in cancer treatment, yet the mechanisms of response to specific therapies have been largely unexplored in vivo. Employing genetic, genomic, and imaging approaches, we examined the dynamics of response to a mainstay chemotherapeutic, cisplatin, in multiple mouse models of human non-small-cell lung cancer (NSCLC). We show that lung tumors initially respond to cisplatin by sensing DNA damage, undergoing cell cycle arrest, and inducing apoptosis—leading to a significant reduction in tumor burden. Importantly, we demonstrate that this response does not depend on the tumor suppressor p53 or its transcriptional target, p21. Prolonged cisplatin treatment promotes the emergence of resistant tumors with enhanced repair capacity that are cross-resistant to platinum analogs, exhibit advanced histopathology, and possess an increased frequency of genomic alterations. Cisplatin-resistant tumors express elevated levels of multiple DNA damage repair and cell cycle arrest-related genes, including p53-inducible protein with a death domain (Pidd). We demonstrate a novel role for PIDD as a regulator of chemotherapy response in human lung tumor cells. |
| first_indexed | 2024-09-23T16:48:36Z |
| format | Article |
| id | mit-1721.1/64761 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:48:36Z |
| publishDate | 2011 |
| publisher | Cold Spring Harbor Laboratory Press in association with The Genetics Society |
| record_format | dspace |
| spelling | mit-1721.1/647612022-09-29T21:38:02Z Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer Oliver, Trudy Mercer, Kim L. Sayles, Leanne C. Burke, James R. Mendus, Diana Lovejoy, Katherine S. Cheng, Mei-Hsin Subramanian, Aravind Mu, David Powers, Scott Crowley, Denise G. Bronson, Roderick T. Whittaker, Charles A. Bhutkar, Arjun (AJ) Lippard, Stephen J. Golub, Todd R. Thomale, Juergen Jacks, Tyler E. Sweet-Cordero, E. Alejandro Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Koch Institute for Integrative Cancer Research at MIT Lippard, Stephen J. Oliver, Trudy Gale Mercer, Kim L. Burke, James R. Lovejoy, Katherine S. Cheng, Mei-Hsin Crowley, Denise G. Whittaker, Charles A. Bhutkar, Arjun (AJ) Lippard, Stephen J. Jacks, Tyler E. Chemotherapy resistance is a major obstacle in cancer treatment, yet the mechanisms of response to specific therapies have been largely unexplored in vivo. Employing genetic, genomic, and imaging approaches, we examined the dynamics of response to a mainstay chemotherapeutic, cisplatin, in multiple mouse models of human non-small-cell lung cancer (NSCLC). We show that lung tumors initially respond to cisplatin by sensing DNA damage, undergoing cell cycle arrest, and inducing apoptosis—leading to a significant reduction in tumor burden. Importantly, we demonstrate that this response does not depend on the tumor suppressor p53 or its transcriptional target, p21. Prolonged cisplatin treatment promotes the emergence of resistant tumors with enhanced repair capacity that are cross-resistant to platinum analogs, exhibit advanced histopathology, and possess an increased frequency of genomic alterations. Cisplatin-resistant tumors express elevated levels of multiple DNA damage repair and cell cycle arrest-related genes, including p53-inducible protein with a death domain (Pidd). We demonstrate a novel role for PIDD as a regulator of chemotherapy response in human lung tumor cells. National Institutes of Health (U.S.) (grant 5-UO1-CA84306) National Cancer Institute (U.S.) (CA034992) 2011-07-07T15:41:25Z 2011-07-07T15:41:25Z 2010-03 2009-12 Article http://purl.org/eprint/type/JournalArticle 0890-9369 1549-5477 http://hdl.handle.net/1721.1/64761 Oliver, Trudy G. et al. “Chronic Cisplatin Treatment Promotes Enhanced Damage Repair and Tumor Progression in a Mouse Model of Lung Cancer.” Genes & Development 24.8 (2010) : 837 -852. https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-2693-4982 en_US http://dx.doi.org/10.1101/gad.1897010 Genes and Development Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Cold Spring Harbor Laboratory Press in association with The Genetics Society Prof. Lippard via Erja Kajosalo |
| spellingShingle | Oliver, Trudy Mercer, Kim L. Sayles, Leanne C. Burke, James R. Mendus, Diana Lovejoy, Katherine S. Cheng, Mei-Hsin Subramanian, Aravind Mu, David Powers, Scott Crowley, Denise G. Bronson, Roderick T. Whittaker, Charles A. Bhutkar, Arjun (AJ) Lippard, Stephen J. Golub, Todd R. Thomale, Juergen Jacks, Tyler E. Sweet-Cordero, E. Alejandro Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer |
| title | Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer |
| title_full | Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer |
| title_fullStr | Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer |
| title_full_unstemmed | Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer |
| title_short | Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer |
| title_sort | chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer |
| url | http://hdl.handle.net/1721.1/64761 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-2693-4982 |
| work_keys_str_mv | AT olivertrudy chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT mercerkiml chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT saylesleannec chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT burkejamesr chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT mendusdiana chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT lovejoykatherines chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT chengmeihsin chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT subramanianaravind chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT mudavid chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT powersscott chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT crowleydeniseg chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT bronsonroderickt chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT whittakercharlesa chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT bhutkararjunaj chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT lippardstephenj chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT golubtoddr chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT thomalejuergen chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT jackstylere chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer AT sweetcorderoealejandro chroniccisplatintreatmentpromotesenhanceddamagerepairandtumorprogressioninamousemodeloflungcancer |