Harnessing the vulnerabilities of p53 mutants in lung cancer – Focusing on the proteasome: a new trick for an old foe?

Figures & data

Figure 1. Wildtype p53 is a tumor suppressor while mutant p53 acquires gain-of-function (GOF) oncogenic activities implicated in several hallmarks of cancer.

Figure 2. Wild type p53 is readily degraded by the proteasome through a multistep process of ubiquitination mediated primarily through the E3 ligase Murine Double Minute 2 (MDM2) and other E4 ligases. Mutant p53 (Mut-p53) evades proteasomal degradation likely due to defective ubiquitination and recognition by the proteasome machinery.

Table 1. Phase I/II and II trials of proteasome inhibitors in lung cancer.

	Study	Arms	Assessed Outcomes
Combination Therapy in Previously Treated Patients	Phase II, previously treated advanced NSCLC, 2006^Citation101	Arm A Bortezomib on D1,4,8, 11 (n = 75) Arm B Bortezomib on D1,4,8,11 plus Docetaxel D1 (n = 80)	Response Rate (%): 8 vs 9 Disease Control Rate (%): 29 vs 54 Median PFS (months):1.5 vs 4 One-year survival (%): 39 vs 33 Median survival (months): 7.4 vs 7.8
	Phase II, previously treated advanced NSCLC 2009^Citation102	Arm A Erlotinib D1 (n = 25) Arm B Erlotinib D1 plus Bortezomib D1 and 8 (n = 25)	Response rate (%):16 vs 9 Median PFS (months): 2.7 vs 1.3 Median OS (months): 7.3 vs 8.5 months 6-month Survival: 56% in both
	Phase II, advanced NSCLC, Performance status of 2, 2009^Citation103	Arm A Docetaxel on D1, 8, 15 plus Cetuximab loading dose on D1 then weekly maintenance dose (n = 32) Arm B Docetaxel on D1, 8, 15 plus Bortezomib on days 1,8, 15. (n = 32)	Response Rate (%):13.3 vs 10.3 Median PFS (months):3.4 vs 1.9 months Median OS (months): 5 vs 3.9
	Phase II, previously treated advanced NSCLC, 2010^Citation104	Arm A Pemetrexed D1 plus Bortezomib D1 and 8 (n = 45) Arm B Pemetrexed D1 alone (n = 45) Arm C Bortezomib D1 and 8 (n = 40)	Response rate (%): 7 vs 4 vs 0 Disease control rate (%): 73 vs 62 vs 43 Median survival OS (months): 8.6 vs 12.7 vs 7.8
	Phase II, previously treated advanced NSCLC, 2011^Citation105	Arm A Docetaxel D1 plus Bortezomib on D1 and 8 (n = 40) Arm B Docetaxel on D1 then Bortezomib on days 2 and 8 (n = 41)	Response Rate (%): 10 vs 10 Disease Control Rate (%): 50 vs 49 Median PFS (weeks): 12 vs 11 Median OS (months): 13.3 vs 10.5
	Phase II, advanced NSCLC as third line therapy, 2014^Citation106	Single Arm biweekly Bortezomib D1, 4, 8, 11 and daily 2-week Vorinostat (n = 18)	Response rate: No objective response. Stable disease (%): 27.8 Median PFS (months): 1.5 Median OS (months): 4.7
	Phase I/II, advanced NSCLC, 2015^Citation107	Single Arm Bortezomib plus Paclitaxel and carboplatin with concurrent thoracic radiation therapy	Response rate (%): 26 Median OS (months): 25 Median PFS (months): 8.4
	Phase II, locally advanced or metastatic NSCLC, 2016^Citation108	Single Arm Bortezomib Plus Gemcitabine/Cisplatin (n = 53)	Response Rate (%): 17 Median PFS (months): 2.5 Median OS (months): 10.6 1-year survival (%): 38.1
Combination Therapy in Chemo-naïve Patients	Phase II, chemo naïve advanced NSCLC, 2009^Citation109	Single Arm Bortezomib plus Gemcitabine and Carboplatin (n = 114)	Response Rate (%): 23 Disease Control Rate: 68 Median PFS (months): 5 Median OS (months): 11 1-year survival (%): 47 2-year survival (%): 19
	Phase I/II, chemo-naïve advanced NSCLC, 2012^Citation110	Single Arm Weekly Bortezomib D1 and 8 Plus standard doses of Carboplatin and Bevacizumab (n = 9)	Response Rate (%): 44 Median PFS (months): 5.5 Median OS (months): 10.9
Single Agent Therapy in Chemo-naïve Patients	Phase II, chemo-naïve advanced NSCLC, 2010^Citation111	Single Arm biweekly Bortezomib Day 1,4,8, 11 every 21 days (n = 14)	Response Rate (%): No objective response Disease Control Rate (%): 21 Median PFS (months): 1.3 Median OS (months): 9.9
	Phase II, chemo-naive advanced NSCLC, 2012^Citation112	Single Arm Bortezomib on D1 and 4 for 2 weeks followed by 10-day rest period (n = 18)	Response Rate (%): No objective response Disease Control Rate: 59 Median PFS (months): 2.4 Median OS (months): 9.8
Single Agent in Previously Treated Patients	Phase II, relapsed or refractory extensive stage SCLC, 2006^Citation113	Single Arm Bortezomib (n = 56; 28 platinum sensitive and 28 platinum refractory)	Response Rate (%): 1 patient Median PFS (months): 1 Median OS (months): 3
	Phase II, advanced-stage bronchioloalveolar carcinoma, 2011^Citation114	Single Arm Biweekly Bortezomib on D1 and 8 (n = 42)	Response Rate (%): No objective response Disease Control Rate (%): 57 Median PFS (months): 5.5 Median OS (months): 13.6
	Phase II, KRAS G12D-mutant lung cancers, 2019^Citation115	Single Arm Biweekly Bortezomib on D1, 4, 8, 11 (n = 16)	Response Rate (%): 6 Disease Control Rate: 5 patients Median PFS (months): 1 month Median OS (months): 13
	Phase I/II, Carfilzomib in advanced solid tumors (NSCLC, SCLC, OVCC, RCC, other)^Citation116	Single Arm 2–10 minute twice weekly infusion of Carfilzomib SCLC (n = 9) NSCLC (n = 15)	Response Rate (%): 0 Disease Control Rate (%):21.5% Stable Disease: 43.1% after 2 cycles.

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