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Dynamic phenotypic switching and group behavior help non-small cell lung cancer cells evade chemotherapy
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  • Arin Nam,
  • Atish Mohanty,
  • Supriyo Bhattacharya,
  • Sourabh Kotnala,
  • Srisairam Achuthan,
  • Kishore Hari,
  • Saumya Srivastava,
  • Linlin Guo,
  • Anusha Nathan,
  • Rishov Chatterjee,
  • Maneesh Jain,
  • Wasim Nasser,
  • Surinder Batra,
  • Govindan Rangarajan,
  • Erminia Massarelli,
  • Herbert Levine,
  • Mohit Kumar Jolly,
  • Prakash Kulkarni,
  • Ravi Salgia
Arin Nam
City of Hope National Medical Center Department of Medical Oncology and Therapeutics Research
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Atish Mohanty
City of Hope National Medical Center Department of Medical Oncology and Therapeutics Research
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Supriyo Bhattacharya
City of Hope Comprehensive Cancer Center Duarte
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Sourabh Kotnala
City of Hope National Medical Center Department of Medical Oncology and Therapeutics Research
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Srisairam Achuthan
City of Hope Comprehensive Cancer Center Duarte
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Kishore Hari
Indian Institute of Science
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Saumya Srivastava
City of Hope National Medical Center Department of Medical Oncology and Therapeutics Research
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Linlin Guo
City of Hope National Medical Center Department of Medical Oncology and Therapeutics Research
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Anusha Nathan
City of Hope National Medical Center Department of Medical Oncology and Therapeutics Research
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Rishov Chatterjee
City of Hope Comprehensive Cancer Center Duarte
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Maneesh Jain
University of Nebraska Medical Center
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Wasim Nasser
University of Nebraska Medical Center
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Surinder Batra
University of Nebraska Medical Center
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Govindan Rangarajan
Indian Institute of Science
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Erminia Massarelli
City of Hope National Medical Center Department of Medical Oncology and Therapeutics Research
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Herbert Levine
Northeastern University College of Engineering
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Mohit Kumar Jolly
Indian Institute of Science
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Prakash Kulkarni
City of Hope National Medical Center Department of Medical Oncology and Therapeutics Research
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Ravi Salgia
City of Hope National Medical Center Department of Medical Oncology and Therapeutics Research

Corresponding Author:[email protected]

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Abstract

Drug resistance, a major challenge in cancer therapy, is typically attributed to mutations and genetic heterogeneity. On the other hand, emerging evidence suggests that dynamic cellular interactions and group behavior also contribute to drug resistance. However, the underlying mechanisms remain poorly understood. Here, we present a new mathematical approach with game theoretical underpinnings that we developed to model real-time growth data of non-small cell lung cancer (NSCLC) cells and discern patterns in response to treatment 68 with cisplatin. We show that the cisplatin-sensitive and cisplatin-tolerant NSCLC cells when co69 cultured in the absence or presence of the drug, display dynamic group behavior strategies. Tolerant cells exhibit a ‘persister-like’ behavior and are attenuated by sensitive cells; they also appear to ‘educate’ sensitive cells to evade chemotherapy. Further, tolerant cells can switch phenotypes to become sensitive, especially at low cisplatin concentrations. Finally, switching treatment from continuous to an intermittent regimen can attenuate the emergence of tolerant cells, suggesting that intermittent chemotherapy may improve outcomes in lung cancer.
10 Sep 2021Submitted to Computational and Systems Oncology
11 Sep 2021Submission Checks Completed
11 Sep 2021Assigned to Editor
28 Sep 2021Reviewer(s) Assigned
13 Nov 2021Review(s) Completed, Editorial Evaluation Pending
17 Nov 2021Editorial Decision: Revise Major